Non-nucleoside reverse transcriptase inhibitors

ABSTRACT

This invention relates to non-nucleoside reverse transcriptase inhibitors active against HIV-1 and having an improved resistance and pharmacokinetic profile. The invention further relates to novel intermediates in the synthesis of such compounds and the use of the compounds in antiviral methods and compositions.

This application is a Divisional of application Ser. No. 10/377,057,filed on Feb. 28, 2003, now U.S. Pat. No. 6,894,177, which is adivisional of application Ser. No. 10/092,752, filed on Mar. 5, 2002 nowU.S. Pat. No. 6,716,850 and for which priority is claimed under 35U.S.C. § 120; and this application claims priority of Application No. SE0100733.5 filed in SWEDEN on Mar. 5, 2001 under 35 U.S.C. § 119; theentire contents of all are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to non-nucleoside reverse transcriptaseinhibitors active against HIV-1 and having an improved resistance andpharmacokinetic profile. The invention further relates to novelintermediates in the synthesis of such compounds and the use of thecompounds in antiviral methods and compositions.

BACKGROUND TO THE INVENTION

Non nucleoside reverse transcriptase inhibitors (NNRTI) bind to anallosteric site on reverse transcriptase and represent an importantdevelopment in the arsenal of drugs against HIV, particularly HIV-1.International patent application WO 93/03022, discloses thiourea NNRTIwhich were later denoted “PETT” (phenyl ethyl thiazolyl thiourea)compounds in J Med Chem 39 6 1329-1335 (1995) and J Med Chem 39 214261-4274 (1996). International patent application nos. WO99/47501,WO/0039095, WO/0056736, WO00/78315 and WO00/78721 describe thiourea PETTderivatives which have allegedly been optimised against a composite RTbinding pocket.

International patent application no WO95/06034 and J Med Chem 424150-4160 (1999) disclose urea isosteres of PETT NNRTIs. Internationalpatent application no WO99/36406 discloses urea NNRTI compounds with afreestanding cyclopropyl bridge, wherein the phenyl left hand wing bearsan obligate 6-hydroxy function and international patent application noWO00/47561 discloses prodrugs of such compounds.

Although the urea and thiourea NNRTI disclosed in the above documentsare active against reverse transcriptase, especially that of HIV-1, thenature of the HIV virus with its extreme lack of replicative fidelityand consequent tendency to rapid resistance development prompts a demandfor further antiretroviral agents with enhanced antiviral performanceagainst problematic drug escape mutants, notably at the RT 100, 103and/or 181 positions.

Additionally, modern HIV therapy regimes, denoted HMRT, Highly ActiveAnti Retroviral Therapy, administer antivirals as combinations of threeor more antivirals of various classes, which combinations areadministered for prolonged periods, if not for life. HAART requires thepatient to follow a complicated dosing schedule with sometimes dozens oftablets per day taken at various times of the day in some cases beforeand in other cases after the ingestion of food. There is thus a need forantiretroviral preparations allowing greater flexibility in dosing tofacilitate patient compliance.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with a first aspect of the invention there are providedcompounds of the formula I:

where

-   R₁ is O, S;-   R₂ is an optionally substituted, nitrogen-containing heterocycle,    wherein the nitrogen is located at the 2 position relative to the    (thio)urea bond;-   R₃ is H, C₁-C₃ alkyl,-   R₄-R₇ are independently selected from H, C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, haloC₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆ alkanoyl,    C₁-C₆ alkoxy, haloC₁-C₆ alkoxy, C₁-C₆ alkyloxy-C₁-C₆ alkyl,    haloC₁-C₆ alkyloxy-C₁-C₆ alkyl hydroxy-C₁-C₆ alkyl, amino-C₁-C₆    alkyl, carboxy-C₁-C₆ alkyl, cyano-C₁-C₆ alkyl, amino, carboxy,    carbamoyl, cyano, halo, hydroxy, keto and the like;-   X is —(CH₂)_(n)-D-(CH₂)_(m)—-   D is —NR₈—, —O—, —S—, —S(═O)— or —S(═O)₂—-   R₈ is H, C₁-C₃ alkyl-   n and m are independently 0 or 1;    and pharmaceutically acceptable salts and prodrugs thereof.

The currently preferred value for R₁ is O, that is a urea derivative,although R₁ as S (ie a thiourea derivative) is also highly potent.

Representative values for R₂ include thiazolyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl,tetrazolyl, piperidyl, piperazinyl and fused rings such asbenzothiazolyl, benzopyridyl, benzodiazolyl, benzimidazolyl, quinolyl,purinyl and the like, any of which can be optionally substituted.

Preferred R₂ values include pyrid-2-yl and thiazol-2-yl.

The optional substituents to R₂ can include up to three substituentssuch as C₁-C₆ alkyl, C₁-C₆ alkoxy, C₂-C₆ alkenyl, C₂-C₈ alkynyl, C₂-C₈alkenoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆ alkyl,C₁-C₄ alkanoyloxy, C₁-C₄ alkylthio, amino (including C₁-C₃alkyl-substituted amino), carboxy, carbamoyl, cyano, halo, hydroxy,aminomethyl, carboxymethyl, hydroxymethyl, nitro, aryl, (such as phenyl,pyrrol-1-yl, tetrazol-5-yl, triazol-4-yl, pyridyl, pyrimidyl, pyrazinyl,imidazolyl, indolyl, piperidyl, piperazinyl, and the like) substituted(as herein defined) aryl, or —SO₂Q or —C(═O)Q, where Q is C₁-C₆ alkyl,halosubstituted C₁-C₆ alkyl, aryl (as herein defined), substituted (asherein defined) aryl or amino. Heteroatoms in R₂ can be derivatised,such as with C₁-C₆ alkyl, oxo and the like. The optional R₂ substituentmay be ortho or meta to the bond to the (thio)urea function but ispreferably para.

Preferred optional substituents to R₂ include ethynyl, phenoxy,pyrrid-1-yl, cyclopropyl, phenyl, halo-substituted phenyl (especiallypara and meta chloro and fluorophenyl), and dimethylamino. Particularlypreferred R₂ substituents include halo (F, Br, Cl and l) and cyano.Preferred halo groups include Cl.

The currently preferred value for R₃ is H.

Preferably R₄ is hydrogen, halo or hydroxy, especially fluoro.

Preferably R₅ is halo, C₁₋₃ alkylcarbonyl, C1-3alkyloxy or H, especiallyfluoro and most preferably H.

Preferably R₆ is hydrogen, halo, C₁-C₃alkyloxy, C1-3alkylcarbonyl, cyanoor ethynyl, especially methoxy or fluoro and most preferably H.

Preferably R₇ is hydrogen, halo, C₁₋₃alkyloxy, or C₁₋₃alkylcarbonyl,most preferably fluoro.

Preferably R₅ and R₆ are H and R₄ and R₇ are halo, most preferably bothare fluoro.

Preferably D is —O—, n is 0, m is 1, R₁ is O, R₂ is substitutedpyrid-2-yl and R₃ is H. An alternative preferred embodiment embracescompounds wherein D is —O—, n is 0, m is 1, R₁ is S, R₂ is substitutedpyrid-2-yl and R₃ is H.

The compounds of formula I may be administered as a racemic mixture, butpreferably the cyclopropyl moiety intermediate the (thio)urea function,X and the phenyl ring (denoted Y below) is at least 75% such as around90% enantiomerically pure with respect to the conformation:

Prefered optical isomers of the compounds of formula I show a negative

optical rotation value. Such isomers, for example when X is —O—CH₂—,tend to elute less rapidly from a chiral chromatagram, for examplechiral AGP 150×10 mm, 5 μm; Crom Tech LTD Colomn, flow rate 4 ml/min,mobile phase 89 vol % 10 mM HOAc/NH₄OAc in acetonitrile. On the basis ofpreliminary x-ray crystallography analysis a presently favoured absoluteconfiguration appears to be:

The currently preferred value for D is —O—. Convenient values for n andm include 1:0 and 1:1. Preferred values of n:m include 0:2 andespecially 0:1, that is a chroman derivative. Particularly preferredcompounds have 5 stereochemistry corresponding to(1S,1aR,7bR)-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl. For the sakeof clarity, it is noted that the structure:

The expression C₁-C_(n) alkyl, where n is 3, 6, 7 etc or lower alkylincludes such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, t-butyl, n-pentyl, n-hexyl, 3-methyl pentyl and the like. Theterm halo refers to chloro, bromo, fluoro and iodo, especially fluoro.C₁-C_(n) alkoxy refers to groups such as methoxy, ethoxy, propoxy,t-butoxy and the like. C₂-C_(n) alkenyl, refers to groups such as vinyl,1-propen-2-yl, 1-buten-4-yl, I-penten-5-yl, 1-buten-1-yl and the like.C₁-C_(n) alkylthio includes methylthio, ethylthio, t-butylthio and thelike. C₁-C_(n) alkanoyloxy includes acetoxy, propionoxy, formyloxy,butyryloxy and the like. C₂-C_(n) alkenoxy includes ethenyloxy,propenyloxy, iso-butoxyethenyl and the like. HaloC₁-C_(n) alkyl(including complex substituents comprising this moiety such ashaloC₁-C_(n) alkyloxy) includes alkyls as defined herein substituted 1to 3 times by a halogen including trifluormethyl, 2-dichloroethyl,3,3-difluoropropyl and the like. The term amine includes goups such asNH₂, NHMe, N(Me)₂ which may optionally be substituted with halogen,C₁-C₇ acyloxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, nitro, carboxy, carbamoyl,carbamoyloxy cyano, methylsulphonylamino and the like. Carboxy,carboxymethyl and carbamoyl include the corresponding pharmaceuticallyacceptable C₁-C₆ alkyl and aryl esters.

Prodrugs of the compounds of formula I are those compounds whichfollowing administration to a patient release a compound of the formulaI in vivo. Typical prodrugs are pharmaceutically acceptable ethers andespecially esters (including phosphate esters) when any of R₄-R₇ or theoptional substituent to R₂ represent an hydroxy function,pharmaceutically acceptable amides or carbamates when any of the R₂substituent or R₄-R₇ represent an amine function or pharmaceuticallyacceptable esters when the R₂ substituent or R₄-R₇ represent a carboxyfunction.

The compounds of formula I can form salts which form an additionalaspect of the invention. Appropriate pharmaceutically acceptable saltsof the compounds of formula I include salts of organic acids, especiallycarboxylic acids, including but not limited to acetate,trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate,malate, pantothenate, isethionate, adipate, alginate, aspartate,benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate,glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate,palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate,tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,organic sulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids.

Hydroxy protecting group as used herein refers to a substituent whichprotects hydroxyl groups against undesirable reactions during syntheticprocedures such as those O-protecting groups disclosed in Greene,“Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York(1981)). Hydroxy protecting groups comprise substituted methyl ethers,for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, t-butyl and other lower alkyl ethers,such as isopropyl, ethyl and especially methyl, benzyl andtriphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, forexample, 2,2,2-trichloroethyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; andesters prepared by reacting the hydroxyl group with a carboxylic acid,for example, acetate, propionate, benzoate and the like.

The invention further provides pharmaceutical compositions comprisingthe compounds of the invention and pharmaceutically acceptable carriersor diluents therefor. Additional aspects of the invention providemethods for the inhibition of HIV comprising administering a compound ofthe formula I to a subject afflicted with or exposed to HIV-1. The HIV-1may comprise a drug escape mutant, such as HIV strain comprising themutations at the 100, 103 and/or 181 mutations, especially K103N.

The invention also extends to the use of the compounds of formula I intherapy, such as in the preparation of a medicament for the treatment ofHIV infections.

In treating conditions caused by HIV, the compounds of formula I arepreferably administered in an amount to achieve a plasma level of around100 to 5000 nM, such as 300 to 2000 nM. This corresponds to a dosagerate, depending on the bioavailability of the formulation, of the order0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosagerate for a normal adult will be around 0.05 to 5 g per day, preferably0.1 to 2 g such as 500-750 mg, in one to four dosage units per day. Aswith all pharmaceuticals, dosage rates will vary with the size andmetabolic condition of the patient as well as the severity of theinfection and may need to be adjusted for concomitant medications.

In keeping with the usual practice with HIV inhibitors it isadvantageous to co-administer one to three additional antivirals toprovide synergistic responses and to ensure complementary resistancepatterns. Such additional antivirals may include AZT, ddI, ddC, D4T,3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil,bis-POC-PMPA, GW420 867X, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097,efavirenz, trovirdine, capravirine, nevirapine, delaviridine,tipranavir, emtricitabine, PFA, H2G (omaciclovir), MIV-606(valomaciclovir stearate), TMC-126, TMC-125, TMC-120, efavirenz,DMP-450, loviride, ritonavir, (including kaletra), lopinavir,saquinavir, lasinavir, indinavir, amprenavir, amprenavir phosphate,nelfinavir and the like, typically at molar ratios reflecting theirrespective activities and bioavailabilities. Generally such ratio willbe of the order of 25:1 to 1:25, relative to the compound of formula I,but may be lower, for instance in the case of cytochrome antagonistssuch as ritonavir.

Compounds of the invention are typically prepared as follows:

Compounds of the general formula (I), wherein R₁, is O (urea) or S(thiourea), R₂ is, for instance, a 5-substituted pyrid-2-yl, and R₃ isH, are prepared by methods shown in Scheme 1. The cyclopropanecarboxylicacid 1-Scheme-1 is converted to the acyl azide and heated to 120° C. toinduce Curtius rearrangement and provide the isocyanate 2-Scheme-1. Theurea 3-Scheme-1 is obtained by coupling of the isocyanate with therelevantly substituted 2-aminopyridine. Hydrolysis of the isocyanate asin step (c) which results in the cyclopropylamine 4-Scheme-1, followedby reaction with a 2-pyridyl isothiocyanate provides the thiourea5-Scheme-1. The isothiocyanate may be prepared from the optionally ringsubstituted 2-aminopyridine by known methods, such as treatment withthiophosgene or thiocarbonyldiimidazole. R₃ variants of formula I areprepared correspondingly using the appropriately amine-substitutedamino-R₂, ie 2-(N-methylamino)pyridine for R₃ as methyl. Many2-aminopyridines are commercially available and others are described inliterature, for example those shown in Scheme 2. R₁=S compounds canalternatively be prepared from the isothiocyanate corresponding to2-Scheme 2 or from amine 3-Scheme 2 and amino-R₂ in conjunction with anRC(═S)R′ both as described in WO 9303022. Although Scheme 1 has beenillustrated with a substituted pyridyl it is readily apparent thatcorresponding couplings can be used for other R₂ variants such asoptionally substituted thiazolyl, pyrazinyl, benzothiazolyl, pyrimidinyletc.

Replacement of the bromine in 5-bromo-2-nitropyridine by a phenoxygroup, followed by reduction of the nitro group affords the2-amino-5-phenoxypyridine. The Sonogashira coupling of2-amino-5-iodopyridine with the terminal alkyne SiMe₃C≡CH in thepresence of catalytic amounts of bis(triphenylphosphine)palladiumdichloride and cuprous iodide as in step (c) provides the2-amino-5-(2-trimethylsilylethynyl)pyridine. Removal of the silyl groupby TBAF yields 2-amino-5-ethynylpyridine which can be coupled to theisocyanate as described in Scheme 1. Alternatively, treatment with TBAFmay be performed on the urea 3-Scheme-1 or thiourea 5-Scheme-1 where R10is —C≡CSiMe₃ to convert R10 to —C≡CH.

Compounds of the general formula (I), wherein R1 is O (urea) or S(thiourea), R2 is, for example, a 5-substituted pyrid-2-yl, R3 is H, Xis -D-CH₂, and wherein the cyclopropyl moiety has the relativeconfiguration

are prepared by methods shown in Scheme 3. Cyclopropanation of thedouble bond in the chromene 1-Scheme-3 with ethyl diazoacetate iscatalyzed by cuprous or rhodium(II) salts such as Cul, (CuOTf)₂-benzene,and Rh₂(OAc)₄ in solvents such as dichloromethane, 1,2-dichloroethane,or chloroform. The reaction provides a diastereomeric mixture of thecyclopropanecarboxylic acid ethyl esters 2-Scheme-3, with the all cisrelative configuration, and its trans isomer 3-Scheme-3. Separation bycolumn chromatography of the cis and trans diastereomers may beaccomplished at this stage, followed by hydrolysis of the isolated2-Scheme-3, such as by refluxing in aqueous methanolic LiOH, to yield aracemic mixture of the all cis cyclopropanecarboxylic acid 4-Scheme-3,as described in step (b). Alternatively, the diastereomeric mixture ofethyl esters may be subjected to hydrolysis, and separation conducted onthe mixture of cyclopropanecarboxylic acids to provide the isolated allcis isomer, as in step (c). Step (d) involves isolation of the cis ethylester 2-Scheme-3 which may also be done by selective hydrolysis of thetrans 3-Scheme-3 at lower temperatures, such as treatment with aqueousmethanolic NaOH at ambient temperature. The isolated cis ethyl ester maythen be hydrolyzed in the usual manner to the cyclopropanecarboxylicacid 4-Scheme-3. The cyclopropanecarboxylic acid is subjected to themethods outlined in Scheme 1 to obtain the urea or thiourea 5-Scheme-3.The chromenes 1-Scheme-3 are prepared by methods shown in Schemes 4, 5,and 6.

Although this scheme 3 has been illustrated with a D=O variant it willbe apparent that corresponding manipulations will be available to theD=S, S=O; S(=O)₂ and D=NR8 variants. When R8 is H, the nitrogen istypically protected with a conventional secondary amine protectinggroup, such as those described in Greene & Wuts Protective Groups inOrganic Synthesis 2^(nd) ed, Wiley NY 1991).

Scheme 4 describes the preparation of chromenes, including many fromcommercially available disubstituted phenols, such as those wherein thesubstitution pattern in the benzene ring is as follows: R4 and R7 arehalo; R4 and R6 are halo; R5 and R7 are halo; R4 is halo and R7 is C₁₋₃alkylcarbonyl; and R4 is hydroxy while R5 is C₁₋₃ alkylcarbonyl.Reaction of the available disubstituted phenol 1-Scheme-4 with3-bromopropyne in the presence of a base, such as K₂CO₃ in acetone orNaH in DMF, results in nucleophilic substitution of the halide toprovide the ether 2-Scheme-4. Ring closure may be accomplished byheating the ether in N,N-dimethylaniline or polyethylene glycol to yieldthe chromene 3-Scheme-4.

Scheme 5 describes the preparation of chromenes, used as startingmaterial in Scheme 3, from the appropriately substituted chromanones,which are readily accessed from commercially available chromanones, forexample those wherein one of the positions in R4 to R7 is substitutedwith halo or C₁₋₃ alkoxy. Conversion of the carbonyl group in4-chromanone 1a-Scheme-5 and to the correponding alcohol by a suitablereducing agent such sodium borohydride in ethanol provides 2-Scheme-5.Refluxing the alcohol with small amounts of acid, such as p-TsOH intoluene, causes dehydration of 2-Scheme-5 to the desired chromene1-Scheme-3. Corresponding manipulations will be available for other Dvariants. For example the corresponding 2H-1-benzothiopyran is readilyprepared from commercially available (substituted) thiochroman-4-ones byreaction with a reductant such as a metal hydride for example lithiumaluminium hydride in an organic solvent such as ether, followed bydehydration such as refluxing with an acid for example potassium acidsulphate or the like.

Chromenes, for use as starting material in Scheme 3, are prepared fromsubstituted o-hydroxybenzaldehydes as shown by methods outlined inScheme 6. Reaction of 1-Scheme-6 with allyl bromide in the presence of abase, such as K₂CO₃ in acetone, results in nucleophilic substitution ofthe halide to provide the ether 2-Scheme-6. Witting reaction transformsthe aldehydic group into the olefin and provides 3-Scheme-6. The pair ofterminal double bonds may undergo metathesis intramolecularly bytreatment with a catalyst such as the ruthenium complex Grubb's catalystin step (c) to produce the chromene. Alternatively 1-Scheme-6 can becyclised directly as shown in step d) in the legend above.

Pd(0) catalyzed coupling of the triflate 1-Scheme-7 leads to thereplacement of the trifluoromethanesulfonyloxy group and theintroduction of other substiutents at R6. Thus, Scheme 7 provides thepreparation of synthesis intermediates for use in scheme 3 to give theurea or thiourea 5-Scheme-3 wherein R6 is cyano, ethynyl, or C₁₋₃alkylcarbonyl.

Convenient routes to compounds wherein X is —CH₂—O— are depicted inScheme 8, where R^(a) and R^(b) are optional substituents R₄-R₇, whichare suitably protected with conventional protecting groups as necessaryand R^(c) is a lower alkyl ester. Optionally substituted phenol1-Scheme-8 which is hydroxy-protected with a protecting group such asmethyl, MOM and the like is reacted with a base such as BuLi or the likein a solvent such as THF or the like and transformed to zinc salt byadding zinc chloride or the like. A catalyst such as Pd(OAc)₂ or thelike is added along with an activated acrylate such as loweralkyl-cis-3-haloacrylate, for example BrCH═CHCOOEt or the like. Thereaction mixture is cooled and a reducing agent such as DIBAL or thelike is added portionwise and quenched to yield 2-Scheme-8. A hydrazonesuch as the p-toluenesulfonylhydrazone of glyoxylic acid chloride or thelike and a base such as N,N-dimethylaniline or the like is added in asolvent such as CH₂Cl₂ or the like followed by the addition of anotherbase such as Et₃N or the like to yield 3-Scheme-8. The reaction productis dissolved in a solvent such as dichloromethane or the like which ispreferably degassed. A chiral Doyle's catalyst such as Rh₂(5-R-MEPy)₄(U.S. Pat. No. 5,175,311, available from Aldrich or Johnson Matthey), orthe like is added to yield 4-Scheme-8 in a high enantiomeric excess suchas greater than 80, preferably greater than 90% ee. Preferably, thiscompound is first reacted with BBr₃ in dichloromethane followed by theaddition of acetonitrile the reaction mixture and finallysodiumhydroxide is added to give 6-Scheme-8. Alternatively, this product(4-Scheme-8) is ring-opened with an electrophile preferably HBr or thelike under in conjunction with an acid such as AcOH or the like. Underacid conditions a spontaneous ring closure takes place to formchromenone 5-Scheme-8. When subjected to basic conditions such as NaOHor the like, the chromenone rearranges to form thechromencyclopropylcarboxylic acid 6-Scheme-8. Alternatively, 4-Scheme-8,for instance when the phenolic protecting group is MOM, can be subjectedto basic conditions such as NaOH, carbon dioxide and a lower alkylhalide such as iPrl in a solvent such as DMSO to open the lactone andyield the alkyl ester 7-Scheme-8. Displacement of the hydroxy protectinggroup and ring closure with the free hydroxymethyl moiety occurs inacidic conditions such as iPrOH/HCl or the like followed by DEAD; PPH₃in an organic solvent such as THF or the like.

Alternatively, in a convergent approach, compound 1-Scheme-8 is reactedwith BuLi and transformed to a zinc salt. This salt reacted with thecyclopropyliodide, 9-Scheme-8, in a palladium-catalyzed reaction to giveafter reaction with Jone's reagent compound 4-Scheme-8. This carboxylicacid is in turn converted to the isocyanate as shown in Scheme 1 andsubsequently to the heteroarylurea or heteroarylthiourea of the FormulaI.

A further aspect of the invention provides novel intermediates useful inthe above described syntheses of the compound of formula I. A preferredgroup of intermediates include compounds of the formula II:

where X and R₄-R₇ are as defined above and R₁₁ is —C(O)OR₁₂, where R₁₂is H or a carboxy protecting group such as a lower alkyl ester; —NCO,—NCS or an amine such as NH₂. A favoured subset of the compounds offormula II have the formula III:

where R₄ and R₇ are independently halo, most preferably fluoro, and R₁₁is —COOH, a lower alkyl ester thereof, isocyanate, isothiocyanate oramino.

A further group of preferred intermediates includes compounds of theformula IV

where R₄ to R₇ are as defined above, PG is an hydroxy protecting groupand PG* is an hydroxy protecting group or together with the adjacent Odefines a keto function.

A preferred subset of compounds of formula IV are those of formula V:

where R₄ and R₇ are independently halo, most preferably fluoro, PG islower alkyl, such as isopropyl, ethyl and most preferably methyl and PG*is lower alkyl such as isopropyl, ethyl and most preferably methyl ortogether with the adjacent O defines a keto group

A still further group of preferred intermediates includes compounds ofthe formula VI:

where R₄-R₇ are as defined above, PG is an hydroxy protecting group andR₁₃ is H, an ester thereof or an hydroxy protecting group. A preferredsubset within formula VI has the formula VII:

where R₄ and R₇ are independently halo, preferably fluoro, PG is loweralkyl, such as isopropyl, ethyl and most preferably methyl and R₁₂ is Hor —C(═O)CH═N═N.

Favoured compounds of formula I include

-   cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,-   cis-1-(5-Cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(5-Chloro-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   cis-1-(5-Bromo-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,-   cis-1-(5-Methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl    )-3-(5-cyano-pyridin-2-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]quinoline-1-yl))-urea,-   cis-1-(5-Cyano-3-methyl-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl    )-3-(5-ethynyl-pyridin-2-yl)-urea,-   cis-1-(5-Bromo-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-phenoxy-pyridin-2-yl)-urea,-   cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea,-   1-(6-Chloro-5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,-   1-(5-Cyano-pyridin-2-yl    )-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,-   cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,-   cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-urea,-   cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea,-   cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-cloro-5-cyano-pyridin-2-yl)-urea,-   cis-1-(5-Cyanopyridin-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea,-   cis    N-[1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thien-1-yl]-N′-(5-cyano-2-pyridinyl)-urea,-   N-[(1S,1aR,7bR) or    (1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopropa[c]-[1]benzothiopyran-1-yl]-N′-(5-cyano-2-pyridinyl)urea,-   cis-N-(5-bromo-2-pyridinyl)-N′-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,-   cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-chloro-2-pyridinyl)urea,-   cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-cyano-2-pyridinyl)urea,-   cis-N-(5-phenoxy-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,-   cis-N-(5-bromo-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,-   cis-N-(5-chloro-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,-   cis-N-(5-cyano-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-fluoro-2-pyridinyl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-iodo-2-pyridinyl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(3-isoxazolyl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(6-fluoro-1,3-benzothiazol-2-yl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(4-pyrimidinyl)urea-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(2-pyrazinyl)urea,-   N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-cyclopropyl-1H-pyrazol-3-yl)urea    and pharmaceutically acceptable salts thereof, especially    enantiomerically enriched, for example greater than 80% by weight,    preferably >90%, such as >97% ee or pure preparations comprising the    (−) enantiomer.

Particularly preferred compound thus include

-   (−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   (−)    cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea;    or-   (−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea;-   (−)-cis-1-(5-Fluoropyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea,-   (−)-cis-1-(5-Fluoropyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea;    and pharmaceutically acceptable salts thereof.

While it is possible for the active agent to be administered alone, itis preferable to present it as part of a pharmaceutical formulation.Such a formulation will comprise the above defined active agent togetherwith one or more acceptable carriers or excipients and optionally othertherapeutic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient.

The formulations include those suitable for rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration, but preferably the formulation is an orally administeredformulation. The formulations may conveniently be presented in unitdosage form, e.g. tablets and sustained release capsules, and may beprepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmaceutical composition comprisingbringing a compound of Formula I or its pharmaceutically acceptable saltin conjunction or association with a pharmaceutically acceptable carrieror vehicle. If the manufacture of pharmaceutical formulations involvesintimate mixing of pharmaceutical excipients and the active ingredientin salt form, then it is often preferred to use excipients which arenon-basic in nature, i.e. either acidic or neutral. Formulations fororal administration in the present invention may be presented asdiscrete units such as capsules, cachets or tablets each containing apredetermined amount of the active agent; as a powder or granules; as asolution or a suspension of the active agent in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or a water inoil liquid emulsion and as a bolus etc.

With regard to compositions for oral administration (e.g. tablets andcapsules), the term suitable carrier includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, stearic acid, glycerol stearate, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring or the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art. A tablet may be made by compression or moulding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the active agent ina free flowing form such as a powder or granules, optionally mixed witha binder, lubricant, inert diluent, preservative, surface-active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may be optionally be coated or scored andmay be formulated so as to provide slow or controlled release of theactive agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

DETAILED DESCRIPTION

Various aspects of the invention will now be illustrated by way ofexample only with reference to the following non-limiting examples.

EXAMPLE 1 (±)cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea

a) ±cis-1,1a,2,7b-Tetrahydro-cyclopropa[c]chromene-1-carboxylic acidethyl ester.

To a mixture of 2H-chromene (4.89 g, 37 mmol) and (CuOTf)₂-benzene (186mg, 0.37 mmol) in 1,2-dichloroethane (80 mL) at 20° C., was addeddropwise (3 h) a solution of ethyl diazoacetate (8.44 g, 74 mmol) in1,2-dichloroethane (20 mL). After 15 min at 20° C., the reaction mixturewas washed with H₂O (100 mL). The H₂O phase was washed with CH₂Cl₂ (50mL) and the solvent of the combined organic phases was removed underreduced pressure. The crude product was column chromatographed (silicagel, 20→50% EtOAc in hexane), to give 1.96 g (24%) of±cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid ethylester and 3.87 g (48%) of±-trans-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acidethyl ester as a byproduct.

¹H-NMR (CDCl₃): 7.26 (d, 1H), 7.10 (dd, 1H), 6.90 (dd, 1H), 6.78 (d,1H), 4.49 (dd, 1H), 4.20 (dd, 1H), 3.97 (q, 2H), 2.44 (dd, 1H), 2.14(dd, 1H), 2.07-1.95 (m, 1H), 1.02 (t, 3H).

b) (±)-cis-1,1a,2,7b-Tetrahydro-cyclopropa[c]chromene-1-carboxylic acid.

A mixture of(±)-cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acidethyl ester (1.96 g, 9.0 mmol), LiOH (539 mg, 22.5 mmol), H₂O (10 mL)and MeOH (20 mL) was heated to reflux for 2 h. The reaction mixture wasconcentrated to about 10 mL, 4N HCl was added dropwise giving a whiteprecipitate. The reaction mixture was extracted with CH₂Cl₂ (3×15 mL)and the solvent of the combined organic phases was removed under reducedpressure. The crude product was crystallized from EtOAc/hexane, to give435 mg (25%) of(±)-cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid asa white solid.

¹H-NMR (CDCl₃): 9.80 (br s, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.89 (dd,1H), 6.77 (d, 1H), 4.45 (dd, 1H), 4.22 (dd, 1H), 2.45 (dd, 1H),2.14-1.98 (m, 2H).

c)(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea.

To a solution of(±)-cis-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic acid(285 mg, 1.5 mmol) and triethylamine (209 μL, 1.5 mmol) in toluene (1.5mL) at 20° C., was added diphenylphosphoryl azide (413 mg, 1.5 mmol).After 30 min at 20° C., the reaction mixture was heated to 120° C. for15 min, where after a solution of 2-amino-5-cyano-pyridine (197 mg, 1.65mmol) in DMF (1 mL) was added. After 3 h at 120° C., the reactionmixture was allowed to assume room temperature. The reaction mixture wasconcentrated under reduced pressure, benzene (20 mL) was added and thereaction mixture was washed with 1N HCl (30 mL), H₂O (30 mL) and brine(30 mL). The solvent of the organic phases was removed under reducedpressure. The crude product was crystallized from EtOH/CH₂Cl₂, to give133 mg (29%) of(±)-cis-1-(5-cyano-pyridin-2-yl)-3-(1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea.

¹H-NMR (DMSO-d₆): 9.78 (s, 1H), 8.31 (d, 1H), 7.99 (dd, 1H), 7.83 (d,1H), 7.43 (d, 1H), 7.27 (d, 1H), 7.09 (dd, 1H), 6.89 (dd, 1H), 6.80 (d,1H), 4.25 (dd, 1H), 4.14 (dd, 1H), 3.43 (m, 1H), 2.35 (dd, 1H), 1.92 (m,1H).

EXAMPLE 2(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-urea

a)(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester

(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester was synthesized analogously to Example 1a from1H-isochromene (3.57 g, 27 mmol), to give 910 mg (15%) of(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.34 (d, 1H), 7.25 (dd, 1H), 7.18 (dd, 1H), 7.03 (d,1H), 4.81 (d, 1H), 4.51 (d, 1H), 4.28 (dd, 1H), 3.95 (q, 2H), 2.43 (dd,1H), 2.05 (dd, 1H), 1.04 (t, 3H).

b)(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid

(±)-cis-1,1a,3,7b-Tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid was synthesized analogously to Example 1b from(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid ethyl ester (436 mg, 2 mmol), to give 86 mg (22%) of(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]-naphthalene-1-carboxylicacid as a white solid. The crude product was column chromatographed(silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (CDCl₃): 8.50 (br s, 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 7.21 (dd,1H), 7.07 (d, 1H), 4.87 (d, 1H), 4.57 (d, 1H), 4.38 (dd, 1H), 2.59 (dd,1H), 2.15 (dd, 1H).

c)(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-urea

(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-ureawas synthesized analogously to example 1c from(±)-cis-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalene-1-carboxylicacid (86 mg, 0.45 mmol). The crude product was column chromatographed(silica gel, 1→5% MeOH in CH₂Cl₂), to give 21 mg (15%) of(±)-cis-1-(5-cyano-pyridin-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]naphthalen-1-yl)-urea.

¹H-NMR (DMSO-d₆): 9.62 (s, 1H), 8.29 (d, 1H), 7.98 (dd, 1H), 7.52-7.44(m, 2H), 7.27-7.05 (m, 4H), 4.69 (d, 1H), 4.45 (d, 1H), 4.05 (dd, 1H),3.25-3.10 (m, 1H), 2.22 (dd, 1H).

EXAMPLE 3(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

a) 1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one

A mixture of 2′,4′-dihydroxy-propiophenone (24.9 g, 0.15 mol),3-bromo-propyne (24.2 g, 0.20 mol) and K₂CO₃ (20.7 g, 0.15 mol) inacetone (500 mL) was refluxed for 12 h. The reaction mixture was allowedassume room temperature and the precipitate was removed by filtration.The filtrate was concentrated under reduced pressure. The crude productwas purified by column chromatography (silica gel, 0→2% MeOH in H₂O), togive 26.2 g (85%) of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one.

¹H-NMR (CDCl₃): 12.80 (s, 1H), 7.69 (d, 1H), 6.52 (m, 2H), 4.72 (d, 2H),2.96 (q, 2H), 2.56 (t, 1H), 1.23 (t, 3H).

3b) 1-(5-Hydroxy-2H-chromen-6-yl)-propan-1-one.

A mixture of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one (19.8 g,97 mmol) and N,N-diethylaniline (100 mL) was heated to reflux for 3 h.The reaction mixture was concentrated under reduced pressure. The crudeproduct was purified by column chromatography (silica gel, 5→10% EtOAcin Hexane) and thereafter recrystallized from EtOAc/Hexane, to give 8.91g (45%) of 1-(5-hydroxy-2H-chromen-6-yl)-propan-1-one.

¹H-NMR (CDCl₃): 13.00 (s, 1H), 7.49 (d, 1H), 6.75 (dt, 1H), 6.27 (d,1H), 5.67 (dt, 1H), 4.86 (dd, 2H), 2.90 (q, 2H), 1.19 (t, 3H).

3c)7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

To a mixture of 1-(5-hydroxy-2H-chromen-6-yl)-propan-1-one (511 mg, 2.5mmol) and (Rh(II)Ac₂)₂ (11 mg, 0.025 mmol) in 1,2-dichloroethane (8 mL)at 20° C., was added dropwise (3 h) a solution of ethyl diazoacetate(571 mg, 5 mmol) in 1,2-dichloroethane (2 mL). After 15 min at 20° C.,the reaction mixture was washed with H₂O (10 mL). The H₂O phase waswashed with CH₂Cl₂ (10 mL) and the solvent of the combined organicphases was removed under reduced pressure. The crude product waspurified by column chromatography (silica gel, 1→5% MeOH in CH₂Cl₂), togive 300 mg (41%) of7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (a 33/64 mixture of cis and trans isomers).

¹H-NMR (CDCl₃): 13.13-13.07 (m, 1H), 7.57-7.49 (m, 1H), 6.41-6.38 (m,1H), 4.65-3.92 (m, 4H), 3.01-1.95 (m, 5H), 1.29-1.08 (m, 6H).

3d)(±)-cis-7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

±cis-7-Hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 2b from7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (299 mg, 1.03 mmol, a 33/64 mixture of cis and transisomers), to give 39.3 mg (15%) of(±)-cis-7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a white solid and(±)-trans-7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a byproduct. The crude product was purified by columnchromatography (silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (DMSO-d₆): 7.67 (d, 1H), 6.35 (d, 1H), 4.57 (dd, 1H), 4.36 (dd,1H), 2.98 (q, 2H), 2.55-2.46 (m, 1H), 2.18-2.00 (m, 2H), 1.10 (t, 3H).

3e)(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas synthesized analogously to Example 1c from±cis-7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (39.3 mg, 0.15 mmol). The crude product was purified by HPLC (C₁₈,5→95% acetonitrile in H₂O), to give 2.9 mg (5.1%) of(±)-cis-1-(5-cyano-pyridin-2-yl)-3-(7-hydroxy-6-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

¹H-NMR (DMSO-d₆): 13.15 (s, 1H), 9.71 (s, 1H), 8.30 (d, 1H), 8.01 (dd,1H), 7.73 (d, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 6.43 (d, 1H), 4.42 (dd,1H), 4.13 (dd, 1H), 3.45-3.32 (m, 1H), 3.01 (q, 2H), 2.49-2.42 (m, 1H),1.97-1.86 (m, 1H), 1.12 (t, 3H).

EXAMPLE 4±cis-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

4a) 1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone

1-(2-Hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone was synthesizedanalogously to Example 3a from 1-(2,4-dihydroxy-phenyl)-ethanone (20 g,131 mmol), to give 22 g (88%) of1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone.

¹H-NMR (CDCl₃): 12.70 (s, 1H), 7.66 (d, 1H), 6.52 (m, 2H), 4.72 (d, 2H),2.58-2.55 (m, 4H).

4b) 1-(5-Hydroxy-2H-chromen-6-yl)-ethanone

1-(5-Hydroxy-2H-chromen-6-yl)-ethanone was synthesized analogously toExample 3b from 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-ethanone (17 g, 89mmol), to give 6.0 g (35%) of 1-(5-hydroxy-2H-chromen-6-yl)-ethanone.

¹H-NMR (CDCl₃): 12.92 (s, 1H), 7.51 (d, 1H), 6.79 (dt, 1H), 6.32 (d,1H), 5.71 (dt, 1H), 4.89 (dd, 2H), 2.55 (s, 3H).

4c)6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (a 40/60 mixture of cis and trans isomers) wassynthesized analogously to Example 3c from1-(5-hydroxy-2H-chromen-6-yl)-ethanone.

¹H-NMR (CDCl₃): 13.05-12.97 (m, 1H), 7.54-7.47 (m, 1H), 6.43-6.33 (m,1H), 4.63-3.94 (m, 4H), 3.02-1.96 (m, 6H), 1.31-1.08 (m, 3H).

4d)6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 1b from6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (2 g, 8.1 mmol, a 40/60 mixture of cis and transisomers), to give 300 mg (17%) of6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (a 40/60 mixture of cis and trans isomers). The crude product waspurified by column chromatography (silica gel, 1→5% MeOH in CH₂Cl₂)

¹H-NMR (CDCl₃): 7.55-7.45 (m, 1H), 6.45-6.30 (m, 1H), 4.65-4.00 (m, 2H),3.05-1.95 (m, 6H).

4e)(±)-cis-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

(±)-cis-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureawas synthesized analogously to Example 1c from6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (300 mg, 1.21 mmol, a 40/60 mixture of cis and trans isomers). Thecrude product was purified by HPLC (C₁₈, 5→95% acetonitrile in H₂O), togive 7.7 mg (17%) of(±)-cis-1-(6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureaand 9.0 mg (20%) of(±)-trans-1-(6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureaas a byproduct.

¹H-NMR (CDCl₃+CD₃OD): 7.98 (d, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.01(d, 1H), 6.40 (d, 1H), 4.43 (dd, 1H), 4.29 (dd, 1H), 3.57 (dd, 1H), 2.69(m, 1H), 2.61 (s, 3H), 2.00-1.86 (m, 1H).

EXAMPLE 5(±)-cis-1-(5-Cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

5a) 1-(4-Fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.

To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., wasadded 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) inDMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol)added to the reaction mixture. After 1 h at 0° C., was the reactionmixture allowed to assume room temperature. The reaction mixture wasextracted with H₂O (100 mL). The H₂O phase was washed with Et₂O (3×100mL) and the solvent of the combined organic phases was removed underreduced pressure. The crude product was purified by columnchromatography (silica gel, CH₂Cl₂), to give 1.40 g (68%) of1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.

¹H-NMR (CDCl₃): 7.64 (dd, 1H), 6.69 (dd, 1H), 6.60 (ddd, 1H), 4.68 (d,2H), 2.85 (q, 2H), 2.58 (t, 1H), 1.03 (t, 3H).

5b) 1-(5-Fluoro-2H-chromen-8-yl)-propan-1-one.

1-(5-Fluoro-2H-chromen-8-yl)-propan-1-one was synthesized analagously toExample 3b from 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one (1.34g, 6.5 mmol), to give 619 mg (46%) of1-(5-fluoro-2H-chromen-8-yl)-propan-1-one.

¹H-NMR (CDCl₃): 7.60 (dd, 1H), 6.67-6.58 (m, 2H), 5.86 (dt, 1H), 4.76(dd, 2H), 2.93 (q, 2H), 1.23 (t, 3H).

5c)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester was synthesized according to method 3c) from1-(5-fluoro-2H-chromen-8-yl)-propan-1-one (619 mg, 3 mmol), to give 142mg (16%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester and(±)-trans-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester as a byproduct.

¹H-NMR (CDCl₃): 7.59 (dd, 1H), 6.65 (m, 1H), 4.50-4.46 (m, 2H), 3.95 (q,2H); 2.89 (q, 2H), 2.57 (dd, 1H), 2.20 (dd, 1H), 1.13-1.03 (m, 1H),1.12-1.01 (m, 6H).

5d)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 1b from(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (140.3 mg, 0.48 mmol), to give 83 mg (65%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a white solid. The crude product was purified by columnchromatography (silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (DMSO-d₆): 12.15 (br s, 1H), 7.46 (dd, 1H), 6.78 (dd, 1H), 4.57(dd, 1H), 4.43 (dd, 1H), 2.93-2.80 (m, 2H), 2.55 (dd, 1H), 2.24 (dd,1H), 2.20-2.10 (m, 1H), 1.02 (t, 3H).

5e)(±)-cis-1-(5-Cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

(±)-cis-1-(5-Cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas synthesized analagously to Example 1c from(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (81.9 mg, 0.31 mmol). The crude product was purified by HPLC (C₁₈,5→95% acetonitrile in H₂O), to give 12 mg (10%) of(±)-cis-1-(5-cyanopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

¹H-NMR (DMSO-d₆): 9.81 (s, 1H), 8.33 (d, 1H), 8.04 (dd, 1H), 7.83 (br s,1H), 7.49-7.40 (m, 2H), 6.89 (dd, 1H), 4.41 (dd, 1H), 4.34 (dd, 1H),3.46-3.38 (m, 1H), 2.76 (q, 2H), 2.56-2.46 (m, 1H), 2.09-1.98 (m, 1H),0.93 (t, 3H).

EXAMPLE 6(±)cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

6a) 6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde.

1M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to asolution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.;Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, NilsGunnar; et al.; J.Med.Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23 mmol)in dichloromethane (30 ml) keeping the reaction temperature at −70 C.The reaction mixture stirred at room temperature overnight andhydrolyzed with water. The organic phase was separated, washed withwater and evaporated in vacuo. The residue was chromatographed (silicagel, EA:Hex, 5:1) to give 3.72 g (94%) of6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.

¹H-NMR (CDCl₃): 11.61 (s, 1H), 10.23 (s, 1H), 7.02 (dd, 1H), 6.55 (app.t, 1H), 3.87 (s, 3H).

6b) 5-Fluoro-8-methoxy-2H-chromene.

6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32 g, 19 mmol) wasdissolved in acetonitrile (20 ml) and DBU (2.97 ml, 19 mmol) was addedfollowed by vinyltriphenylphosphine bromide (7.2 g, 19 mmol). Thereaction mixture was heated under reflux for 48 h, diluted with waterand extracted with ether (3×50 ml). The organic phase was washed withwater, 10% sodium hydroxide, water and brine and evaporated in vacuo.The residue was submitted to column chromatography (silica gel, EA:Hex,1:20) yielding 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).

¹H-NMR (CDCl₃): 6.65 (m, 2H), 6.54 (t, 1H), 5.83 (dt, 1H), 4.88 (dd,2H), 3.83 (s, 3H).

6c)(±)-cis-7-Fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

The title compound was synthesized analogously to example 3c from5-fluoro-8-methoxy-2H-chromene.

¹H-NMR (CDCl₃): 6.7-6.5 (m, 2H), 4.48 (m, 2H), 3.99 (m, 2H), 3.80 (s,3H), 2.57 (app.t, 1H), 2.20 (app.t, 1H), 2.05 (m, 1H), 1.08 (t, 3H).

6d)(±)-cis-7-Fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

The title compound was synthesized analogously to example 1b from(±)-cis-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 6.7-6.5 (m, 2H), 4.48 (m, 2H), 3.80 (s, 3H), 2.61 (app.t, 1H), 2.17 (app. t, 1H), 2.06 (m, 1H).

6e)(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound was synthesized analogously to Example 1c from(±)-cis-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (62 mg, 0.17 mmol). Yield 38 mg (40%).

¹H-NMR (CDCl₃): 10.06 (br. s, 1H), 9.40 (br. d, 1H), 8.11 (d, 1H), 7.70(dd, 1H), 6.91 (d, 1H), 6.68 (m, 2H), 4.48 (dd, 1H), 4.28 (dd, 1H),3.90-3.72 (m, 4H), 2.64 (app. T, 1H), 1.96 (m, 1H).

EXAMPLE 7(±)-cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

7a) 1-Chloro-4-fluoro-2-prop-2-ynyloxy-benzene.

The title compound was synthesized analogously to example 15a) from2-chloro-5-fluorophenol (2.5 g). Yield 2.8 g (90%).

¹H-NMR (CDCl₃): 7.32 (dd, 1H), 6.85 (dd, 1H), 6.68 (m, 1H), 4.77 (d,2H), 2.58 (t, 1H).

7b) 5-Fluoro-8-chloro-2H-chromene.

The title compound was synthesized analogously to Example 15b) from1-chloro-4-fluoro-2-prop-2-ynyloxy-benzene (2.8 g). Yield 0.97 g (35%).

¹H-NMR (CDCl₃): 7.09 (dd, 1H), 6.63 (dt, 1H), 6.56 (t, 1H), 5.84 (dt,1H), 4.95 (dd, 2H).

7c)±cis-7-Fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

The title compound was synthesized analogously to Example 15c) from5-Fluoro-8-chloro-2H-chromene.

¹H-NMR (CDCl₃): 7.14 (dd, 1H), 6.60 (t, 1H), 4.51 (m, 2H), 4.01 (m, 2H),2.60 (app. t, 1H), 2.23 (t, 1H), 2.09 (m, 1H), 1.08 (t, 3H).

7d)(±)-cis-7-Fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

The title compound was synthesized analogously to example 15d) from(±)-cis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester 850 mg). Yield 43 mg (96%).

¹H-NMR (CDCl₃): 8.86 (br. s, 1H), 7.13 (dd, 1H), 6.59 (t, 1H), 4.50 (m,2H), 2.63 (t, 1H), 2.23-2.05 (m, 2H).

7e)±cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound was synthesized analogously to example 1c from(±)-cis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (63 mg). Yield 52 mg (56%).

¹H-NMR (CDCl₃): 9.79 (br. s, 1H), 9.34 (br. s, 1H), 8.22 (d, 1H), 7.72(dd, 1H), 7.17 (dd, 1H), 6.87 (d, 1H), 6.67 (t, 1H), 4.54 (dd, 1H), 4.33(dd, 1H), 3.84 (app. q, 1H), 2.68 (dd, 1H), 2.00 (m, 1H).

EXAMPLE 8±cis-1-(5-Chloro-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea

±cis-1-(5-Chloro-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea(15 mg, 24%) was prepared according to the procedure described inexample 1c, from±cis-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene)-1-carboxylicacid (40 mg, 0.16 mmol) and 2-amino-5-chloropyridine (76 mg, 0.57 mmol).

¹H NMR (400 MHz,CDCl₃) δ ppm: 9.29 (brs, 1H), 9.26 (brs 1H), 7.84 (d,1H), 7.47 (dd, 1H), 7.16 (dd, 1H), 6.76 (d, 1H), 6.67 (dd, 1H), 4.65(dd, 1H), 4.34 (dd, 1H), 3.82 (dd, 1H), 2.62 (dd, 1H), 1.96 (m, 1H)

EXAMPLE 9±cis-1-(5-Bromo-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea

±cis-1-(5-Bromo-pyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-yl)-urea(13 mg, 19%) was prepared according to the procedure described inexample 1c, from±cis-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene)-1-carboxylicacid (40 mg, 0.16 mmol) and 2-amino-5-bromopyridine (99 mg, 0.57 mmol).

¹H NMR (400 MHz, CDCl₃) δ ppm: 9.27 (brs, 1H), 9.02 (brs, 1H), 7.95 (d,1H), 7.60 (dd, 1H), 7.16 (dd, 1H), 6.70 (d, 1H), 6.67 (dd, 1H), 4.50(dd, 1H), 4.35 (dd, 1H), 3.81 (dd, 1H), 2.63 (dd, 1H), 1.97 (m, 1H)

EXAMPLE 10±cis-1-(5-Cyano-pyridin-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

10a) Trifluoro-methanesulfonic acid 4-formyl-3-hydroxy-phenyl ester.

A solution of triflic anhydride (1.77 ml, 10.5 mmol) in dichloromethane10 ml) was added to a mixture of 2,4-dihydroxybenzaldehyde (1.38 g, 10mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (30 ml) at−70 C. Dry ice bath was removed and the reaction mixture was stirred for2 h at room temperature. The reaction mixture was diluted withdichloromethane, washed with water, brine and evaporated in vacuo. Thecrude product was purified by column chromatography (silica gel, EA:Hex,1:6) to give 1.55 g of trifluoro-methanesulfonic acid4-formyl-3-hydroxy-phenyl ester (57%).

¹H-NMR (CDCl₃): 11.28 (s, 1H), 9.93 (s, 1H), 7.67 (d, 1H), 6.95 (m, 2H).

10b) Trifluoro-methanesulfonic acid 3-allyloxy-4-formyl-phenyl ester.

Potassium carbonate (1.6 g, 11.5 mmol) and allyl bromide (1 ml, 11.5mmol) were added to a solution of trifluoro-methanesulfonic acid4-formyl-3-hydroxy-phenyl ester (1.55 g, 5.7 mmol) in acetone (50 ml).The reaction mixture was stirred at 55 C for 2 h, filtered andevaporated in vacuo. The residue was chromatographed (silica gel,EA:Hex, 1:20) to give 1.3 g (73%) of trifluoro-methanesulfonic acid3-allyloxy-4-formyl-phenyl ester.

¹H-NMR (CDCl₃): 10.47 (s, 1H), 7.93 (d, 1H), 6.95 (d, 1H), 6.90 (s, 1H),6.05 (m, 1H), 5.47 (d, 1H), 5.40 (d, 1H), 4.69 (d, 2H).

10c) Trifluoro-methanesulfonic acid 3-allyloxy-4-vinyl-phenyl ester.

Methyltriphenylphosphonium bromide (1.95 g, 5.45 mmol) was added to asuspension of sodium hydride (60% in oil) (0.25 g, 6.3 mmol) in THF (35ml) at 0 C and it was stirred for 30 min at room temperature. To theabove solution was added solution of trifluoro-methanesulfonic acid3-allyloxy-4-formyl-phenyl ester (1.3 g, 4.2 mmol) in THF (15 ml), andthe reaction mixture was stirred for 2 h at room temperature. Thereaction mixture was diluted with hexane and extracted with water.Organic phase was washed with brine and evaporated. Silica gel columnchromatography (EA:Hex, 1:20) afforded trifluoro-methanesulfonic acid3-allyloxy-4-vinyl-phenyl ester (0.68 g, 53%).

¹H-NMR (CDCl₃): 7.51 (d, 1H), 7.02 (dd, 1H), 6.85 (dd, 1H), 6.77 (d,1H), 6.05 (m, 1H), 5.76 (dd, 1H), 5.43 (m, 1H), 5.32 (m, 2H), 4.58 (dt,2H).

10d) Trifluoro-methanesulfonic acid 2H-chromen-7-yl ester.

To a solution of trifluoro-methanesulfonic acid3-allyloxy-4-vinyl-phenyl ester (0.68 g, 2.2 mmol) in dichloromethane (5ml) was added Ru-catalyst (Grubb's catalyst) (36 mg, 2 mol %), and thereaction mixture was stirred for 2 h at room temperature. After thatperiod the reaction was complete (GC) and the reaction mixture was usedin the next step without any work-up. Analytical sample was obtainedafter removal of the solvent by silica gel column chromatography(EA:Hex, 1:20).

¹H-NMR (CDCl₃): 6.97 (d, 1H), 6.76 (dd, 1H), 6.68 (d, 1H), 6.39 (dt,1H), 5.81 (dt, 1H), 4.98 (dd, 2H).

10e)±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

Rh(OAc)₂ (19 mg, 2 mol %) was added to the above solution (10d) and thesolution of EDA (0.44 ml, 4.4 mmol) in 1 ml of dichloromethane was addedwith a syringe pump over 5 h at room temperature. When the reaction wascomplete (GC) dichloromethane was evaporated, the residue was dissolvedin ethyl acetate and washed with saturated ammonium chloride solutionand brine. Organic phase was evaporated and crude mixture of cis- andtrans-isomers (1:1.3) was separated by column chromatography (silicagel, EA:Hex, 1:6) to give 0.4 g (50%) of±cis-5-trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.29 (d, 1H), 6.82 (dd, 1H), 6.73 (d, 1H), 4.51 (dd,1H), 4.29 (dd, 1H), 3.98 (m, 2H), 2.45 (t, 1H), 2.19 (t, 1H), 2.05 (m,1H), 1.03 (t, 3H).

10f)±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (154 mg, 0.42 mmol), Pd(OAC)₂ (9 mg, 10 mol %) and PPh₃(44 mg, 40 mol %) were mixed in DMF (4 ml) and gentle stream of nitrogenpassed through reaction mixture for 10 min. Zn(CN)₂ (74 mg, 0.63 mmol)was added, vial was sealed and the reaction mixture was stirred at 120 Covernight. The reaction mixture was diluted with ethyl acetate andextracted with saturated ammonium chloride. Organic phase was evaporatedand residue chromatographed (silica gel, EA:Hex 1:5) to give 53 mg (52%)of ±cis-5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.33 (d, 1H), 7.19 (dd, 1H), 7.05 (d, 1H), 4.50 (dd,1H), 4.25 (dd, 1H), 3.99 (q, 2H), 2.46 (t, 1H), 2.25 (t, 1H), 2.11 (m,1H), 1.06 (t, 3H).

10g)±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (53 mg, 0.22 mmol) and NaOH (35 mg, 0.88 mmol) weredissolved in mixture methanol water (1:1) (5 ml). Reaction mixture wasstirred at 60 C for 30 min. Methanol was evaporated in vacuo and 20 mlof water was added. Resulting solution was extracted with ether. Waterphase was concentrated, acidified with 1M HCl to pH˜2 and extracted withether. The organic phase was washed with brine and evaporated to give 42mg (90%) of±cis-5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

¹H-NMR (CDCl₃): 7.33 (d, 1H), 7.19 (dd, 1H), 7.06 (d, 1H), 4.51 (dd,1H), 4.31 (dd, 1H), 2.53 (app. t, 1H), 2.27 (app. t, 1H), 2.16 (m, 1H).

10h)±cis-1-(5-Cyano-pyridin-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

±cis-5-Cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (42 mg, 0.19 mmol) and TEA (0.032 ml, 0.21 mmol) were dissolved in3 ml of toluene. DPPA (0.046 ml, 0.21 mmol) and 2-amino-5-cyano-pirydine(25 mg, 0.21 mmol) were added. The reaction mixture was heated underreflux with stirring for 3 h. The resulting precipitate was filtered andwashed with hot ethanol (3 ml) yielding 41 mg (63%) of±cis-1-(5-cyano-pyridin-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

¹H-NMR (DMSO-d₆): 9.86 (s, 1H), 8.48 (d, 1H), 8.07 (dd, 1H), 7.97 (br.s, 1H), 7.51 (d, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 7.34 (dd, 1H), 4.39(dd, 1H), 4.19 (dd, 1H), 3.57 (app. q, 1H), 2.54 (app. t, 1H), 2.09 (m,1H).

EXAMPLE 11±cis-1-(5-Cyano-pyridin-2-yl)-3-(5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

11a)±cis-5-Trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (152 mg, 0.41 mmol), DPPP (38 mg, 20 mol %), Pd(dba)₂(24 mg, 10 mol %), Cul (3 mg, 4 mol %) were mixed in 3 ml oftriethylamine and gentle stream of nitrogen passed through reactionmixture for 10 min. Trimethylsilyl-acetylene (0.088 ml, 0.62 mmol) wasadded, vial was sealed and the reaction mixture was stirred at 120 Covernight. The reaction mixture was diluted with ethyl acetate, washedwith water, brine and evaporated. The residue was purified by silica gelcolumn chromatography (EA:Hex, 1:15) to give 0.1 g (77%) of±cis-5-trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

¹H-NMR (CDCl₃): 7.15 (d, 1H), 7.01 (dd, 1H), 6.88 (d, 1H), 4.47 (dd,1H), 4.16 (dd, 1H), 3.96 (q, 2H), 2.38 (t, 1H), 2.13 (t, 1H), 2.01 (m,1H), 1.04 (t, 3H), 0.22 (s, 9H).

11b)±cis-5-Ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

±cis-5-Trimethylsilanylethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (0.1 g, 0.32 mmol) and sodium hydroxide (0.076 g, 1.9mmol) were dissolved in mixture of methanol:water (1:1) (5 ml). Thereaction mixture was heated at 60 C for 5 h, then it was acidified with1M HCl to pH˜2 and extracted with ether. The organic phase was washedwith brine and evaporated to give 66 mg (97%) of )±cis-5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

¹H-NMR (CDCl₃): 7.17 (d, 1H), 7.03 (dd, 1H), 6.91 (d, 1H), 4.45 (dd,1H), 4.23 (dd, 1H), 3.02 (s, 1H), 2.46 (t, 1H), 2.13 (t, 1H), 2.07 (m,1H).

11c)±cis-1-(5-Cyano-pyridin-2-yl)-3-(5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound was synthesized analogously to example 10h from±cis-5-ethynyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (66 mg, 31 mmol). Yield 53 mg (52%).

¹H-NMR (DMSO-d₆): 9.88 (s, 1H), 8.41 (d, 1H), 8.06 (dd, 1H), 7.86 (br.s, 1H), 7.46 (d, 1H), 7.32 (d, 1H), 7.02 (dd, 1H), 6.93 (d, 1H), 4.31(dd, 1H), 4.16 (dd, 1H), 4.12 (s, 1H), 3.47 (q, 1H), 2.43 (app. t, 1H),2.00 (m, 1H).

EXAMPLE 12±cis-1-(5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

12a)±cis-5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

±cis-5-Trifluoromethanesulfonyloxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (117 mg, 0.32 mmol), DPPP (7.3 mg, 50 mol %), Pd(OAc)₂(2 mg, 25 mol %) and triethyl amine (0.09 ml, 0.64 mmol) were mixed inDMF (3 ml) and gentle stream of nitrogen passed through reaction mixturefor 10 min. Butyl vinyl ether (0.21 ml, 1.6 mmol) was added, vial wassealed and the reaction mixture was stirred at 100 C for 2 h. 5% HCl (5ml) was added and the reaction mixture was stirred at room temperaturefor 30 min. Resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with saturated ammonium chloride andevaporated. The residue was purified by silica gel column chromatography(EA:Hex, 1:5) to give 76 mg (91%) of±cis-5-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylic

¹H-NMR (CDCl₃):7.52 (dd, 1H), 7.36 (d, 1H), 7.34 (d, 1H), 4.51 (dd, 1H),4.21 (dd, 1H), 3.98 (q, 2H), 2.53 (s, 3H), 2.47 (t, 1H), 2.23 (t, 1H),2.08 (m, 1H), 1.05 (t, 3H).

12b)±cis-5-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

The title compound was synthesized analogously to example 10g from±cis-5-acetyl-1,1 a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (76 mg, 29 mmol). Yield 66 mg (97%).

¹H-NMR (CDCl₃): 7.52 (dd, 1H), 7.37 (d, 1H), 7.34 (d, 1H), 4.52 (dd,1H), 4.26 (dd, 1H), 2.55 (s, 3H), 2.53 (t, 1H), 2.25 (t, 1H), 2.13 (m,1H).

12c)±cis-1-(5-Cyano-pyridin-2-yl)-3-(5-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound was synthesized analogously to example 10h from±cis-5-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (66 mg, 28 mmol). Yield 58 mg (59%).

¹H-NMR (DMSO-d₆): 9.87 (s, 1H), 8.42 (d, 1H), 8.05 (dd, 1H), 7.88 (br.s, 1H), 7.52 (dd, 1H), 7.49-7.44 (m, 2H), 7.37 (d, 1H), 4.39 (dd, 1H),4.18 (dd, 1H), 3.55 (q, 1H), 2.55-2.50 (m, 4H, superimposed on residualDMSO-d₆ peak), 2.07 (m, 1H).

EXAMPLE 13±cis-1-(5-Methoxy-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

The title compound was synthesized analogously to example 10 from2-hydroxy-4-methoxybenzaldehyde.

¹H-NMR (CDCl₃): 8.44 (br. s, 1H), 8.06 (d, 1H), 7.70 (dd, 1H), 7.18 (d,1H), 6.82 (br. d, 1H), 6.55 (dd, 1H), 6.36 (d, 1H), 4.32 (dd, 1H), 4.24(dd, 1H), 3.76 (s, 3H), 3.58 (q, 1H), 2.36 (dd, 1H), 1.86 (m, 1H).

EXAMPLE 14±cis-1-(5-Cyano-pyridin-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]quinoline-1-yl))-urea

a) N-Acetyl-1,2-dihydroquinoline.

Quinoline (19.37 g, 150 mmol) was dissolved in anhydrous diethyl ether(500 ml) and cooled to 0° C. under inert atmosphere. DIBAL, 1.5 M intoluene (100 ml, 150 mmol) was added dropwise over 2 hrs and thereaction mixture was stirred at 0° C. for 30 min. Acetic anhydride (500ml) was added dropwise over 30 min and the reaction mixture was stirredat 0° C. for 30 min. H₂O was added cautiously. The reaction mixture wasextracted with diethyl ether and concentrated to giveN-acetyl-1,2-dihydroquinoline (11.5 g, 44%).

b)±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester.

±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester was prepared according to the procedure described inexample 1a, from N-acetyl-1,2-dihydroquinoline (10 g, 58 mmol) Theproduct was purified by column chromatography on silica (EtOAc/hexane5%→50%) to give±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester (2.0 g, 13%).

c)±cis-(N-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid.

±cis-(N-Acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid (425 mg, 24%) was prepared according to the procedure described inexample 1b, from±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid ethyl ester (2.0 mg, 7.7 mmol).

d)±cis-1-(5-Cyano-pyridin-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]quinoline-1-yl))-urea.

±cis-1-(5-Cyano-pyridin-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxa-cyclopropa[a]quinoline-1-yl))-urea(250 mg, 40%) was prepared according to the procedure described inexample 1c, from±cis-(N-acetyl-1,1a,2,7b-tetrahydro-cyclopropa[c]quinoline)-1-carboxylicacid (416 mg, 1.8 mmol).

¹H NMR (250 MHz, DMSO-d₆) δ ppm: 9.51 (brs, 1H), 8.30 (d 1H), 8.01 (dd,1H), 7.54 (dd, 1H), 7.44, (dd, 1H), 7.36 (d, 1H), 7.23-7.18 (m, 3H),4.10 (d, 1H), 3.60 (dd, 1H), 3.12-3.05 (m, 1H), 2.37 (tr, 1H), 2.0-1.92(m, 4H)

EXAMPLE 15+/−-cis-1-(5-Cyanopyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

15a) 2,4-Difluoro-2-propynyloxybenzene.

Commercially available 2,5-difluorophenol (20 g , 0.15 mol), K₂CO₃ (53g, 0.38 mol) and commercially available 3-bromopropyne (45 g, 0.38 mol)were dissolved in acetone (300 ml), refluxed over night, cooled andfiltrated. The solvent was removed and the crude product, dissolved inether and washed with water and brine. The organic phase was evaporatedand the crude product was re-dissolved in a small amount of ether andfiltrated through a column of basic Al₂O₃. Evaporation and drying gave20 g (80%) of 2,4-difluoro-2-prop-ynyloxy-benzene

15b) 5,8-Difluoro-2H-chromene.

2,4-Difluoro-2-propynyloxybenzene (20 g, 0.12 mol) was dissolved inN,N,-diethyl aniline (100 ml) and heated under argon atmosphere at 225deg. Celcius with an oil-bath for 6-8 h. Ether (150 ml) was added andthe aniline was removed by extraction using 2 M HCl_((aq)). Purificationby chromatography (silica gel, n-hexane) gave 5,8-difluoro-2H-chromene5.8 g (29%)

15c)+/−cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

5,8-Difluoro-2H-chromene (5 g, 0.03 mol), (Rh(II)Ac₂)₂ (0.39 g, 0.00089mol) was dissolved in 1,2-dichloroethane (60 ml) or ethanol-freechloroform. Ethyl diazoacetate (9.4 ml, 0089 mol) in the same solventwas added dropwise over a period of approximately 5 h under N₂atmosphere. The solvent was then removed under vacuum and the mixturewas taken upp in ethyl acetate, washed with NaHCO₃(aq), water and brineand the solvent removed. The product (33% cis, 66% trans) was purifiedby hromatography (0→10% ethyl acetate in n-hexane) to give 2.2 g of thetitle compound (30%).

15d)cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

Cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (2 g, 0.008 mol) was heated in 1M LiOH inmethanol-water (25%) at 80 deg. for 2 h. The volume was reduced to halfand acidified. Extraction with ether followed by chromatography (silicagel, ether) gave pure title compound (35%)e)(/−)cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

(+/−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas prepared analogously to Example 1c but usingcis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (0.2 g, 0.00088 mol) to give 0.130 g (42%) of pure title compound.The crude product was purified by extraction between 0.01 M HCl (aq) andethyl acetate and chromatography (silica gel, 0→1% MeOH in Ether). Thesolvent was evaporated and the solid washed with a cold solution of 50%aceton in n-hexane.

¹H-NMR (CDCl₃-MeOD): 8.16 (d, 1H), 7.72 (dd, 1H), 6.97-6.86 (m, 2H),6.69-6.61 (m, 1H), 4.47 (dd, 1H), 4.31 (dd, 1H), 3.75 (m, 1H), 2.65 (t,1H), 2.05-1.96 (m, 1H).

EXAMPLE 16(+/−)-cis-1-(5-Cyano-3-methyl-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

(+/−)-cis-1-(5-Cyano-3-methyl-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas prepared analogously to Example 1c but usingcis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (168 mg, 0.74 mmol) and 6-amino-5-methyl-nicotinonitrile (109 mg,0.82 mmol ) to give(+/−)-cis-1-(5-cyano-3-methyl-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea52 mg of (20%). The crude product was purified by extraction between0.01 M HCl (aq) and ethyl acetate and chromatography (silica gel, 0→25%MeOH in Ether). The solvent was evaporated and the solid washed with 25%aceton in n-hexane.

¹H NMR (CDCl3-MeOD): 8.02 (d, 1H), 7.61 (dd, 1H), 6.97-6.87 (m, 1H,6.70-6.62 (m, 1H), 4.48 (dd, 1H), 4.30 (dd, 1H), 3.78 (t, 1H), 3.37 (s,3H), 2.66 (t, 1H), 2.03 (m, 1H).

EXAMPLE 17+/−-cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

+/−-cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas prepared analogously to Example 1c but usingcis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (90 mg, 0.4 mmol) and 6-amino-5-chloropyridine (51 mg, 0.44 mmol)to give+/−-cis-1-(5-chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea(50 mg, 35%). The crude product was purified by extraction between 0.01M HCl (aq) and ethyl acetate-ether (1:1) and chromatography (silica gel,ether).

¹H NMR (CDCl₃): 9.2 (broad s, NH), 8.6 (broad s, NH), 7.81 (dd, 1H),7.48 (dd, 1H), 6.89 (m, 1H), 6.75 (d, 1H), 6.69 (m, 1H), 4.45 (dd, 1H),4.33 (dd, 1H), 3.75 (m, 1H), 2.61 (m, 1H), 1.97 (m, 1H).

EXAMPLE 18(+/−)-cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-ethynyl-pyridin-2-yl)-urea

+/−cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-ethynyl-pyridin-2-yl)-ureawas prepared analogously to Example 1c) but usingcis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (100 mg, 0.4 0.44 mmol) and5-trimethylsilanylethynyl-pyridine-2-ylamine (93 mg, 0.49 mmol) to give(25 mg, 17%). The crude product was purified by extraction between 0.01M HCl (aq) and ethyl acetat-ether (1:1) and chromatography (silica gel,ether). The mixture obtained (containing the title compound togetherwith silylated compound) was stirred with Bu₄N⁺F⁻ in 25% water in THFfor 30 min and the chromatography was repeated to obtain pure+/−cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-ethynyl-pyridin-2-yl)-urea.

¹H NMR (CDCl₃): 9.2 ( broad s, NH), 7.95 (d, 1H), 7.59 (dd, 1H), 7.48(broad s, 1H), 6.89 (td, 1H), 6.64 (td, 1H), 6.57 (d, 1H), 4.46 (dd,1H), 4.33 (dd, 1H), 3.78 (q, 1H), 3.11 (s, 1H), 2.62 (t, 1H), 1.99-1.97(m, 1H)

EXAMPLE 19(+/−)-cis-1-(5-Bromo-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

+/−-cis-1-(5-Bromo-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-ureawas prepared analogously to Example 1c but usingcis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol) and 6-amino-5-bromopyridine (42 mg, 0.24 mmol )to give+/−-cis-1-(5-bromo-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea(50 mg, 35%). The crude product was purified by extraction between 0.01M HCl (aq) and ethyl acetate and chromatography (silica gel, ether.

¹H NMR (CDCl₃): 9.2 (broad s, NH), 7.88 (d, 1H), 7.75 (broad s, 1H),7.60 (dd, 1H), 6.89 (m, 1H), 6.63 (td, 1H), 6.59 (d, 1H), 4.45 (dd, 1H),4.33 (dd, 1H), 3.78 (q, 1H), 2.62 (t, 1H), 1.98 (m, 1H).

EXAMPLE 20+/−cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-phenoxy-pyridin-2-yl)-urea

(+/−)-cis-1-(4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-phenoxy-pyridin-2-yl)-ureawas prepared analogously to Example 1c) but usingcis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (60 mg, 0.26 mmol) and 6-amino-5-phenoxypyridine ( 56 mg, 0.29mmol) to give 32 mg (30%) of the title compound. The crude product waspurified by extraction between 0.01 M HCl (aq) and ethyl acetate andchromatography (silica gel, 20% ether in n-hexane)

¹H NMR (CDCl₃): 7.60 (d, 1H), 7.45 (broad s, 1H), 7.37-7.34 (m, 2H),7.27-7.24 (m, 2H), 7.14-7.11 (m, 1H), 6.94-9.92 (m, 2H), 6.79-7.74 (m,1H), 6.63 (d, 1H), 6.59-6.55 (m, 1H), 4.43 (dd, 1H), 4.36 (dd, 1H), 3.75(q, 1H), 2.59 (t, 1H), 1.98-1.94 (m, 1H).

EXAMPLE 21(+/−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea

cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (113 mg, 0.5 mmol), DPPA (118.6 μl, 0.55 mmol) and TEA (70.7 μl,0.55 mmol) was refluxed in toluene (2 ml) for 1 h. Dioxane (3 ml) andHCl_((aq)) (1.5 ml, 6M) was then added and the reaction mixture was leftfor 1 h. at 50° C. Ether and water was then added and the layersseparated. The water phase was washed with ether and then made alkalinewith ammonia_((aq)). Extraction with dichlorometane and drying gave theintermdiate4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1ylamine, whichwas directly treated with 6-isothiocyanato-nicotinonitril (34 mg, 0.55mmol) in acetonitrile (4 ml) at RT over-night. The precipitated crystalswere filtrated off and washed with cold acetonitrile to give 30 mg (17%)of pure(+/−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thioureaLC-MS: m/z 358.9

EXAMPLE 221-(6-Chloro-5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea

1-(6-Chloro-5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)ureawas prepared analogously to Example 1c) but usingcis-5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (280 mg, 1.21 mmol) and 6-amino-2-chloro-3-cyanopyridine (203 mg,1.33 mmol) to give the title compound in small amount. The crude productwas purified by extraction between 0.01 M HCl (aq) and ether andchromatography (silica gel, ether) and washed with acetone-ether.

¹H NMR (DMSO-d₆): 10 (br s, NH), 8.20 (d, 1H), 7.70 (d, 1H), 6.9 (brs,NH), 6.8 (m, 1H), 6.6 (m, 1H), 4.4 (dd, 1H), 4.2 (dd, 1H), 3.2 (m, 1H),2.4 (t, 1H), 1.9 (m, 1H).

EXAMPLE 231-(5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea

1-(5-cyano-pyridin-2-yl)-3-(5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)ureawas prepared analogously to Example 1c) but usingcis-5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (390 mg, 1.72 mmol) and 2-amino-5-cyanopyridine (226 mg, 1.89mmol). The crude product was purified by extraction between 0.01 M HCl(aq), recrystallization, several washings with aceton and acetonitrileand chromatography (silica gel, 1% EtOAc in ether) to give 28 mg of thetitle compound.

¹H NMR (CDCl3-MeOD): 8.16 (t, 1H), 7.78 (dd, 1H), 7.09 (d, 1H),6.56-6.34 (m, 2H), 4.34 (m, 2H), 3.54 (t, 1H), 2.57 (dd, 1H), 2.00-1.90(m, 1H).

EXAMPLE 24cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureawas prepared analogously to Example 1c) but usingcis-4-bromo-7fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (178 mg, 0.62 mmol) and 2-amino-5-cyanopyridine (0.81 mg, 0.68mmol) The crude product was chromatographed (silica, ether) and washedwith acetone to give 40 mg (16%) ofcis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea.

¹H NMR (CDCl₃): 9.85 (s, 1H), 9.3 (s, 1H), 7.75 (dd, 1H), 7.33 (dd, 1H),6.95 (d, 1H), 6.65 (t, 1H), 4.05 (dd, 1H), 4.32 (dd, 1H), 3.35 (t, H),2.65 (t, 1H), 2.05-1.95 (m, 1H).

EXAMPLE 25cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cycloprona[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-urea

cis-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-ureawas prepared analogously to Example 1c but usingcis-4-bromo-7fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (178 mg, 0.62 mmol) and 2-amino-6-chloro-5-cyanopyridine (105 mg,0.68 mmol). The crude product was chromatographed (silica, 0→1% MeOH inether) and washed with acetone-hexane to give 40 mg (13%) ofcis-1-(4-bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-urea.

¹H NMR (CDCl₃): 9.90 (s, 1H), 8.30 (s, 1H), 7.75 (d, 1H), 7.25 (d, 1H),6.60 (t, 1H), 4,5 (dd, 1H), 4.35 (dd, 1H), 3.5 (m, 1H), 2.65 (m, 1H),2.1-1.95 (m, 1H).

EXAMPLE 26cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea

cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-ureaurea was prepared analogously to Example 1c but usingcis-4-bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (177 mg, 0.62 mmol) and 2-amino-5-cyanopyridine (81 mg, 0.68 mmol).The crude product was extracted between ether and 0.02 M HCl_((aq)),chromatographed (silica, 0→1% MeOH in ether) and washed withacetone-hexane to give 42 mg (17%) ofcis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(5-cyano-pyridin-2-yl)-urea.

¹H NMR (CDCl3-MeOD): 8.37 (m, 1H), 7.75 (dd, 1H), 7.14 (dd, 1H), 7.05(dd, 1H), 6.93 (d, 1H), 4.56 (dd, 1H), 4.21 (dd, 1H), 3.77 (t, 1H), 2.42(dd, 1H), 2.00 (m, 1H).

EXAMPLE 27cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-cloro-5-cyano-pyridin-2-yl)-urea

cis-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-chloro-5-cyano-pyridin-2-yl)-ureawas prepared analogously to Example 1c) but usingcis-4-bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (177 mg, 0.62 mmol) and 2-amino-6-chloro-5-cyanopyridine (105 mg,0.68 mmol). The crude product was extracted between ether and 0.01 MHCl_((aq)), chromatographed (silica, 0→1% MeOH in ether) and washed withacetone-hexane to give 46 mg (17%) ofcis-1-(4-bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-3-(6-cloro-5-cyano-pyridin-2-yl)-urea.

¹H NMR (CDCl3): 9.41 (s 1H,), 8.28 (dd, 1H), 7.04 (dd, 1H), 4.54 (dd,1H), 4.25 (dd, 1H), 3.50 (m, 1H), 2.41 (dd, 1H), 2.06-1.98 (m, 1H).

EXAMPLE 28Cis-1-(5-cyanopyridin-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea

cis-1-(5-Cyano-pyridin-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)ureawas prepared analogously to Example 1c) but usingcis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (168 mg, 0.8 mmol) and 2-amino-5-cyanopyridine (105 mg, 0.88 mmol).The crude product was extracted between ether and 0.01 M HCl_((aq))chromatographed (silica, 0→1% MeOH in ether) and washed withaceton-hexane to give only 10 mg (4%) ofcis-1-(5-cyano-pyridin-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)urea.

¹H NMR (CDCl3-MeOD): 8.16 (d, 1H), 7.73 (dd, 1H), 7.05 (dd, 1H), 6.96(d, 1H), 6.84 (td , 1H), 6.76 (dd, 1H), 4.39 (dd, 1H), 4.17 (dd, 1H),3.67 (t, 1H), 2.39 (dd, 1H), 1.96-1.92 (m, 1H).

EXAMPLE 29 Intermediates

29a) 6-Fluorochroman-4-ol

6-Fluorochroman-4-one (10 g, 61 mmol) was dissolved in ethanol (100 ml).NaBH₄ (excess) was added and cooled on icebath. The mixture was thenleft in room temperature for 2 h, folowed by reflux for 4 h.Purification by chromatography (silica gel, ether-hexane, 1:5) gave 8. g(80%) pure 6-fluoro-chroman-4-ol.

29b) 6-Fluoro-2H-chromene

6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acidn (1 g)were dissolved in toluene and refluxed over-night with subsequent waterremoval. The mixture was then cooled and washed with NaHCO₃ (aq) andpurified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) ofpure 6-fluoro-2H-chromene.

29c)±/−cis-6-Fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This Compound was prepared analogously tocis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 6-fluoro-2H-chromene to give 1.9 (29%) of thetitle compound.

29d)Cis-6-Fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

This compound was prepared analogously tocis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid but usingcis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (1.9 g, 8 mmol) to give 350 mg (21%) of purecis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

29e) 1-Bromo4-fluoro-2-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g(87%)

29f) 2-Bromo4-fluoro-1-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-4-fluoro-phenol(15 g, 78 mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15. g(84%).

29g) 1,3-difluoro-5-prop-2-ynyloxy-benzene

This compound was prepared analogously to2,4-difluoro-2-propynyloxybenzene but using 3,5-difluoro-phenol (14 g,107 mmol) to give 1,3-difluoro-5-prop-2-ynyloxy-benzene 12 g (67%).

9h) 8-Bromo-6-fluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (15 g, 65 mmol ) of 2-bromo-4-fluoro-1-prop-2-ynyloxybenzenetogive the title compound (7 g, 46%)

29i) 8-Bromo-5-fluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (15 g, 65 mmol) of 1-bromo-4-fluoro-2-prop-2-ynyloxybenzene togive the title compound (3.7 g, 25

29j) 5,7-Difluoro-2H-chromene

This compound was prepared analogously to 5,8-difluoro-2H-chromene butusing (18 g, 107 mmol) of 1,3-difluoro-5-prop-2-ynyloxybenzene andPEG-200 as solvent to give the title compound (4 g, 23%).

29k)+/−cis-4-Bromo-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 5 g (22 mmol) of 8-bromo 6-fluoro-2H-chromeneto give 1.9 g (30%) ofcis-6-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

29l)+/−cis-4-Bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 3.5 g (15.3 mmol) of8-bromo-5-fluoro-2H-chromene to give 1.6 g (33%) of+/−cis-4-bromo-7-fluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

29m)+/−cis-5,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

This compound was prepared analogously to+/−cis-4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester but using 2 g (12 mmol) of 5,7-difluoro-2H-chromene togive 0.9 g (29%) of+/−cis-5,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

EXAMPLE 30 Optical isomers ofcis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

Racemic(+/−)-cis-1-(5-cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea(see Example 15) was separated into optically active compounds by usinga chiral AGP 150×10 mm, 5 μm; Crom Tech LTD Colomn. The flow rate wasset to 4 ml/min. The mobile phase was 89 vol % 10 mM HOAc/NH₄OAc inacetonitrile. Two elution peaks are seen. The isomer eluting second,typically exhibiting negative rotation is particularly active.

Without in any way wishing to be bound by this observation, it isbelieved that the more slowly eluting isomer bears the absoluteconfiguration depicted below, which has been established by reference tox-ray crystallographic coordinates of the unsubstituted analogue ofExample 1 liganded within reverse transcriptase enzyme. Theconfiguration depicted below is clearly seen in the solved structure,whereas the other enantiomer is not present.

EXAMPLE 31 (−)cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

Racemic(+/−)-cis-1-(5-chloropyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea(see Example 17) was separated into optically active compounds by usinga chiral AGP 150×10 mm, 5 μm; Crom Tech LTD Colomn. The flow rate wasset to 4 ml/min. The mobile phase was 89 vol % 10 mM HOAc/NH₄OAc inacetonitrile. Two elution peaks at 27.7 min and 33.2 min are seen. Thetitle isomer eluting at 33.2 min, typically exhibiting negativerotation, is particularly active.

EXAMPLE 32(−)cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropafclchromen-1-yl)-urea

a) Resolution of the racemiccis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

0.32 g (1.32 mmol) of racemiccis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was dissolved in hot acetonitrile (50 ml) and(1R,2R)-2-benzyloxycyclopentylamine (0.25 g, 1.32 mmol) was added. Theresulting solution was left for crystallization. After few hours themother liquor was decanted and crystals were washed with acetonitrile.The second crystallization from acetonitrile gave 92 mg of purediastereomeric salt. The salt was treated with 1M HCl and resultingmixture was extracted with ethyl acetate. The organic phase was washedwith water, brine and evaporated to give 0.05 g of enantiomericcis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

b)(−)cis-1-(5-Cyano-pyridin-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound was synthesized analogously to Example 1c) fromenantiomericcis-7-fluoro-4-chloro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (50 mg). Yield 60.2 mg (84%). [α]_(D)=−0.388 (c=0.5, CHCl₃).

EXAMPLE 33+/−cis-N-(5-cyano-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

a) 1,4-dichloro-2-(2-propynyloxy)benzene

2,5-Dichlorophenol (8 g, 49 mmol) was mixed with potassium carbonate(13.6 g, 98 mmol) and 80% solution of propargyl bromide in toluene (11ml, 98 mmol) in acetone (100 ml) and stirred overnight at roomtemperature. The precipitate was removed by filtration and washed withacetone. The acetone solution obtaind was concentrated by rotaryevaporation and kept under vacuum for 5 h. The product was obtained asyellow oil with quantitative yield. It was used for futhertransformations without additional purification.

b) 5,8-dichloro-2H-chromene

1,4-Dichloro-2-(2-propynyloxy)benzene was degassed and heated atstirring under argon for 4 h at 224° C. The reaction mixture was thendistilled in Kugelrohr apparatus (150-175° C./4.1×10⁻² mbar) to give3.58 g of desired product as white solid. Yield 36% from startingdichlorophenol.

c) +/−cis-ethyl4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate

5,8-Dichloro-2H-chromene (3.15 g, 16 mmol), (Rh(II)Ac₂)₂ (30 mg, 0.1 mol%) was dissolved in degassed dry methylene chloride (3 ml). Ethyldiazoacetate (3 ml, 2 eq.) in the same solvent was added by a syringe atthe flow rate 0.4 ml/h over a period of approximately 5 h under N₂atmosphere. The reaction mixture was then washed with NH₄Cl (aq), waterand brine and the solvent removed. The product (45% cis, 55% trans) waspurified by chromatography on silica (200 g, ethyl acetate/n-hexane1:15) to give 0.9 g of the pure cis product (racemate). Yield 20%.M⁺=287.

¹H-NMR (CDCl₃): 7.15 (d, 1H, J=8.5Hz), 6.91 (d, 1H, J=8.8Hz), 4.59 (dd,1H, J₁=12.02, J₂=7.03), 4.48 (dd, 1H, J₁=12.02, J₂=4.10), 4.07-3.94 (m,3H), 2.62 (t, 1H, J=8.8 Hz), 2.27 (t, 1H, J=8.36 Hz), 2.20-2.12 (m, 1H),1.1 (t, 3H).

d)+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

+/−cis-Ethyl4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate wasmixed with methanol (3 ml) and water solution of NaOH (1.5 eq., 3 ml)and heated at stirring for 1.5 h at 60° C. The extraction of basicreaction mixture into hexane showed that no starting material present.The reaction mixture was acidified with excess of 3M HCl solution(pH=1). The precipitate formed was collected by suction and washed withwater. White solid obtained was dried under high vacuum (yield 80%).

e)+/−cis-N-(5-cyano-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (100 mg, 0.39 mmol) was mixed with toluene (3 ml), triethylamine(1.1 eq), 5-cyano-2-aminopyridine (1.1 eq), DPPA (1.1 eq) and bubbledwith argon for about 5 min. The reaction mixture was then heated atstirring at 115° C. for 3 h under argon. The reaction mixture wasconcentrated by rotary evaporation and mixed with small amount of dryethanol. The precipitate formed was collected by suction and washed withethanol (2×2 ml) Desired product (+/−cis isomer) was obtained asbeige-white powder (65 mg, yield 45%).

¹H-NMR (DMSO-d₆): 9.83 (s, 1H), 8.34 (d, 1H), 8.03 (dd, 1H), 7.75 (br s,1H), 7.44 (d, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 4.43 (dd, 1H), 4.18 (dd,1H), 3.55-3.45 (m, ˜1H overlapped with H₂O signal), 2.54 (dd, 1H),2.10-2.02 (m, 1H).

EXAMPLE 34+/−cis-N-(5-chloro-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

+/−cis-N-(5-chloro-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)ureawas synthesized analogously to Example 33 from+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (100 mg, 0.39 mmol) and 2-amino-5-chloropyridine (1.1 eq) to give66 mg of product as white powder. Yield 44%.

¹H-NMR (DMSO-d₆): 9.47 (s, 1H), 7.98 (d, 1H), 7.86 (br s, ˜1H), 7.83(dd, 1H), 7.30 (d, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 4.44 (dd, 1H), 4.18(dd, 1H), 3.55-3.48 (m, 1H), 2.54 (dd, 1H), 2.10-2.02 (m, 1H).

EXAMPLE 35+/−cis-N-(5-bromo-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

+/−cis-N-(5-bromo-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)ureawas synthesized analogously to Example 33 from+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (100 mg, 0.39 mmol) and 2-amino-5-bromopyridine (1.1 eq) to give 35mg of product as grey powder. Yield 21%.

¹H-NMR (DMSO-d₆): 9.47 (s, 1H), 7.97 (d, 1H), 7.86 (br s, ˜1H), 7.83(dd, 1H), 7.30 (d, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 4.43 (dd, 1H), 4.18(dd, 1H), 3.55-3.48 (m, 1H), 2.54 (dd, ˜1H overlapped with DMSO signal),2.08-2.01 (m, 1H).

EXAMPLE 36+/−cis-N-(5-phenoxy-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

+/−cis-N-(5-phenoxy-2-pyridinyl)-N′-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)ureawas synthesized analogously to Example 33 from+/−cis-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (58 mg, 0.22 mmol) and 2-amino-5-phenoxypyridine (1.1 eq) to give49 mg of product as slightly brownish powder. Yield 49%.

¹H-NMR (CDCl₃): 9.30 (br s, 1H), 8.26 (s, 1H), 7.53 (d, 1H), 7.35 (m,2H), 7.25 (dd, 1H), 7.16-7.10 (dd, ˜1H overlapped with CHCl₃ signal),7.05 (d, 1H), 6.97-6.90 (m, 3H), 6.72 (d, 1H), 4.46 (dd, 1H), 4.30 (dd,1H), 2.73 (m, 1H), 2.63 (dd, 1H), 2.05-1.95 (m, 1H).

EXAMPLE 37+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-cyano-2-pyridinyl)urea

a) 5-chloro-2-fluorophenol

5-Chloro-2-fluoroaniline (10 g, 68 mmol) was dissolved in 6M sulfuricacid and cooled in ice/brine bath to −5° C. The solution of NaNO₂ (5.2g, 76 mmol) in minimum amount of water was added dropwise to the stirredsuspension at the temperature not higher then −2° C. After the additionclear yellow solution formed was allowed to stir for additional 30 minat cooling. CuSO₄ was dissolved water (80 ml) and mixed with sulfuricacid (32 ml). The diazonium salt solution was added dropwise to thepreheated (160° C.) cuprous sulfate solution and the product was removedfrom the reaction flask by steam distillation. The reaction took about 2h to be complete. The water/phnol solution was extracted into ether,washed with brine and dried over Na₂SO₄. Concentration gave 4 g of crudephenol (40%).

b) 4-chloro-1-fluoro-2-(2-propynyloxy)benzene

4-Chloro-1-fluoro-2-(2-propynyloxy)benzene was synthesized analogouslyto Example 33a from (4 g, 27 mmol) 4-chloro-1-fluorophenol to give 4.6 gof product (purified by column chromatography on silica, ethylacetate/n-hexane 1:15) as yellow oil. Yield 90%.

c) 5-chloro-8-fluoro-2H-chromene

5-Chloro-8-fluoro-2H-chromene was synthesized analogously to Example33b) from 4-chloro-1-fluoro-2-(2-propynyloxy)benzene (4.6 g, 25 mmol) togive 1 g of product (purified by column chromatography on alumina, ethylacetate/n-hexane 1:15) as colourless oil. Yield 22%.

d) ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate

Ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylatewas synthesized analogously to Example 33c from5-chloro-8-fluoro-2H-chromene (1 g, 5.4 mmol) to give 360 mg of +/−cisproduct (purified by column chromatography on silica, ethylacetate/n-hexane 1:20) as white solid. Yield 25%.

e)+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

+/−cis-7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 33d from ethyl+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylate(360 mg, 1.3 mmol) to give 259 mg of +/−-cis acid (80%).

f)+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-cyano-2-pyridinyl)urea

+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-cyano-2-pyridinyl)ureawas synthesized analogously to Example 33e from+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (60 mg, 0.25 mmol) and 2-amino-5-chloropyridine (1.1 eq) to give 59mg of product as white powder. Yield 66%.

¹H-NMR (DMSO-d₆): 9.47 (br s, 1H), 7.89 (d, 1H), 7.80 (br s, 1H), 7.74(dd, 1H), 7.32 (d, 1H), 7.16-7.05 (m, 2H), 4.39 (dd, 1H), 4.16 (dd, 1H),3.55-3.48 (m, 1H), 2.51 (dd, ˜1H overlapped with DMSO signal), 2.08-2.01(m, 1H).

EXAMPLE 38+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-chloro-2-pyridinyl)urea

+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-chloro-2-pyridinyl)ureawas synthesized analogously to Example 5 from+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (60 mg, 0.25 mmol) and 2-amino-5-chloropyridine (1.1 eq) to give 59mg of product as white powder. Yield 65%.

¹H-NMR (DMSO-d₆): 9.47 (br s, 1H), 7.89 (d, 1H), 7.80 (br s, 1H), 7.74(dd, 1H), 7.32 (d, 1H), 7.16-7.04 (m, 2H), 4.39 (dd, 1H), 4.16 (dd, 1H),3.55-3.48 (m, 1H), 2.51 (dd, ˜1H overlapped with DMSO signal), 2.06-2.01(m, 1H).

EXAMPLE 39+/−cis-N-(5-bromo-2-pyridinyl)-N′-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)urea

+/−cis-N-(5-bromo-2-pyridinyl)-N′-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)ureawas synthesized analogously to Example 32e from+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (60 mg, 0.25 mmol) and 2-amino-5-bromopyridine (1.1 eq) to give 56mg of product as white powder. Yield 55%.

¹H-NMR (DMSO-d₆): 9.46 (br s, 1H), 7.96 (d, 1H), 7.83 (dd, 1H), 7.81 (brs, 1H), 7.27 (d, 1H), 7.16-7.04 (m, 2H), 4.38 (dd, 1H), 4.17 (dd, 1H),3.55-3.48 (m, 1H), 2.51 (dd, ˜1H overlapped with DMSO signal), 2.07-2.00(m, 1H).

EXAMPLE 40+/−cis-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-phenoxy-2-pyridinyl)urea

+/−cis-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl)-N′-(5-phenoxy-2-pyridinyl)ureawas synthesized analogously to Example 32e from+/−cis-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (60 mg, 0.25 mmol) and 2-amino-5-phenoxypyridine (1.1 eq) to give76 mg of product as slightly brownish powder. Yield 73%.

¹H-NMR (CDCl₃): 9.33 (brs, 1H), 7.93 (s, 1H), 7.51 (d, 1H), 7.38-7.32(m, 2H), 7.25 (dd, ˜1H overlapped with CHCl₃ signal), 7.16-7.10 (m, 1H),6.96-6.88 (m, 3H), 6.79 (dd, 1H), 6.68 (d, 1H), 4.45 (dd, 1H), 4.25 (dd,1H), 3.75-3.70 (m, 1H), 2.61 (dd, 1H), 2.05-1.95 (m, 1H).

EXAMPLE 41 N-[( 1S,1aR,7bR) or(1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopropa[c]-[1]benzothiopyran-1-yl]-N′-(5-cyano-2-pyridinyl)urea

a) 3,4-dihydro-2H-1-benzothiopyran-4-ol

A solution of thiochroman-4-one (9 g) in ether (27 ml) was added slowlyto a mixture of lithium aluminium hydride (0.53 g) in ether (54 ml).After the end of the addition, the mixture was refluxed for 2 hours. Thereaction mixture was cooled and ice was added, followed by water and bya solution of 20% H₂SO₄. The water phase was washed twice with ether.The ether phase was washed twice with NaOH 2N, and once with water,dried over MgSO₄ and evaporated. The clear oil (8.9 g) crystallisedafter few hours. Rdt=97%

b) 2H-1-benzothiopyran and 4H-1-benzothiopyran

4-Thiochromanol (8.9 g) and potassium acid sulfate (0.89 g) were placedin a flask and evacuated to 1 mm. The flask was put in a bath heated at90° C. until the alcohol melted. The magnetic stirrer was started andthe bath slowly brought to 120° C. Dehydration was rapid and a mixtureof the product and water distilled and was collected in a ice-cooledreceiver. The product was taken up in ether and dried. The crude product(7 g, Rdt=88%) wasn't purified. The NMR showed the presence of 10% ofthe 4H-1-benzothiopyran.

c) Ethyl ester1,1a,2,7b-tetrahydro-cyclopropa[c][1]benzothiopyran-1-carboxylic acid,(1S,1aR,7bR) or (1R,1aS,7bS)

Ethyl diazoacetate was added slowly to 500 mg of thiochromene at 140 C.The reaction was followed by Gas chromatography and stopped when allstarting material was consumed (about 7 hours). The residue was purifiedby flash chromatography (5% ether in hexane). The cis isomer (46.5 mg,Rdt=6%) was identified by NMR spectroscopy.

d) 1,1a,2,7b, tetrahydro-cyclopropa[c][1]benzothiopyran-1-carboxylicacid, (1S,1aR,7bR) or (1R,1aS,7bS)

A mixture of the cis isomer (46.5 mg), LiOH (4 eq., 19 mg) in 5 ml ofmethanol/25% H₂O was refluxed for 1 hour. After evaporation of thesolvent under vacuum, the residue was dissolved in water and washed withether. The water phase was acidified with concentrated HCl, andextracted twice with dichloromethane. After drying, the organic phasewas evaporated and gave the desired acid (30 mg). Rdt=73%.

e) N-[(1S,1aR,7bR) or(1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopropa[c][1]benzothiopyran-1-yl]-N′-(5-cyano-2-pyridinyl)urea

The cis acid (30 mg) was refluxed for 4 hours in toluene (2 ml) inpresence of Et₃N (0.02 ml), diphenyl phosphonic azide (0.03 ml) and2-amino 6-cyanopyridine (19.5 mg). After cooling, the toluene phase waswashed with water, followed by a solution of HCl (0.01 M). The organicphase was dried and evaporated. The residue was purified by flashchromatography (EtOAc 2/Hexane 1) and gave 10 mg of the desiredcompound. Rdt=22%.

¹H (DMSO-d₆): 1.96 (1H, m); 2.30 (1H, t, 8.6); 2.71 (1H, ddt, 13.65,6.24); 3.24 (2H, m); 7.19 (3H, m); 7.37 (1H, dd, 7.4, 1.56); 7.42 (1H,dd, 9.0, 3.1); 7.60 (1H, NH); 8.02 (1H, dd, 9.0, 2.3); 8.15 (1H, s);9.89 (1H, NH)

Mass: 322 (M⁺.), 321 (M−H)

EXAMPLE 42(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid

a) (2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol.

A solution of BuLi (2.5M) in hexane (9.6 ml; 0.024 mol) was added to astirred solution of 2,5-difluoroanisol (2.88 g, 0.02 mol) in dry THF (30ml) at −70 C, followed after 2 h by solution of zinc chloride (3.6 g ;0.026 mol) in dry THF (50 ml). The reaction temperature was allowed toraise to room temperature and then stirring was maintained at roomtemperature for 30 min. Pd(OAc)₂ (8 mg; 0.2 mol %) was added, followedby ethyl cis-3-bromoacrylate (3.58 g ; 0.02 mol). The reaction mixturewas placed in preheated oil bath and heated under reflux for 1 h. Theresulting reaction mixture was chilled to −78 C and 60 ml (0.06 mol) ofDIBAL (1M solution in hexanes) was added dropwise. The stirring wascontinued at −78 C for 2 h and 1 h at room temperature. The reaction wasquenched with water and all solids were dissolved by addition of HCl.The organic phase was diluted with ether, separated, washed with 5N HCl,brine and evaporated in vacuo. The residue was Kugelrohr distilled(1.5×10⁻² mbar, 150 C) to give 3.7 g (92%) of crude(2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol, which contains ˜6%of other regioisomers. The crude product was used in the next stepwithout further purification.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.77 (m, 1H); 6.31 (app. d, 1H); 6.12(app. dt, 1H); 4.08 (br. t, 2H); 3.89 (d, 3H); 1.80 (br. t, 1H).

b) (2Z)-3-(3,6-difluoro-2-methoxyphenyl)prop-2enyl diazoacetate

The p-toluenesulfonylhydrozone of glyoxylic acid chloride (5.16 g; 0.02mol) was added to a solution of(2Z)-3-(3,6-difluoro-2-methoxyphenyl)-2-propen-1-ol (3.6 g; 0.018 mol)in dry CH₂Cl₂ (50 ml) at −5 C, and N,N-dimethylaniline (2.5 ml; 0.02mol) was added slowly. After stirring for 30 min at −5 C, Et₃N (12 ml;0.09 mol) was added slowly. The resulting mixture was stirred for 15 minat −5 C and then for 30 min at room temperature, whereupon water (˜50ml) was added. The organic phase was separated washed with water, brineand concentrated in vacuo. Flash chromatography (silica, EA:Hex; 1:15)gave 3.86 g (80%) of product as a yellow solid.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.76 (m, 1H); 6.41 (app. d, J=12.2 Hz;1H); 6.00 (app. dt, J=12.2; 6.10 Hz; 1H); 4.71 (br. s, 1H); 4.67 (dt,2H); 3.89 (d, 3H).

c)(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one.

(2Z)-3-(3,6-difluoro-2-methoxyphenyl)prop-2enyl diazoacetate (3.45 g,0.013 mol) was dissolved in 100 ml of dried degassed dichloromethane andadded dropwise to the solution of chiral Doyle catalyst (Aldrich, alsoavailable from Johnsson Matthey, 10 mg, 0.1 mol %) in 50 ml ofdichloromethane under argon at ambient temperature over a period of ˜6h. The initial blue color had turned to olive by the end of theaddition. The reaction mixture was concentrated in vacuo and the crudeproduct was purified by flash chromatography (silica, EA:Hex, 1:5→1:1)to give 2.72 g (88%) of(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-oneas colorless solid. Enantiomeric purity could be checked on this stageusing Chiracel OD column, 10% IPA in hexane —94% ee.

¹H-NMR (CDCl₃): 7.00 (m, 1H); 6.72 (m, 1H); 4.33 (dd, 1H); 4.10 (d, 1H);4.02 (d, 3H); 2.66 (m, 2H); 2.37 (t, 1H).

d)(1S,1aR,7bS)-1-(bromomethyl)-4,7-difluoro-1a,7b-dihydrocyclopropa[c]chromene-2(1H)-one.

(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one(130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) andheated in a sealed vessel at stirring for about 4 h at 90° C. Thereaction mixture was then cooled down, mixed with water and extractedinto diethyl ether (3×20 ml). Ether extract was washed with sat. sodiumbicarbonate solution and brine. Dried over magnesium sulfate.Concentration gave 160 mg of white solid material. 98% yield.

¹H-NMR (CDCl₃): 7.08 (m, 1H); 6.88 (m, 1H); 3.44 (dd, 1H); 3.06 (t, 1H);2.96 (dd, 1H); 2.64 (dd, 1H); 2.46 (m, 1H).

e)(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid.

(1S,1aR,7bS)-1-(bromomethyl)-4,7-difluoro-1a,7b-dihydrocyclopropa[c]chromen-2(1H)-one(360 mg, 1.2 mmol) was mixed with the solution of NaOH (0.1 g, 2.5 mmol)in 5 ml of water and heated at stirring for 1 h at 90° C. Aftercompletion the reaction mixture was cooled down and extracted intodiethyl ether (2×20 ml). Water phase was acidified with conc. HCl. Theprecipitate formed was collected by filtration to give 180 mg of pureproduct. Mother liquor was extracted into ether and washed with brine,dried over magnesium sulfate. Concentration gave additional 70 mg ofproduct (containing up to 15% of impurities). Overall yield about 92%.

¹H-NMR (CDCl₃): 6.86 (m, 1H); 6.54 (m, 1H); 4.48 (m, 2H); 2.62 (t, 1H);2.20 (t, 1H); 2.11 (m, 1H).

EXAMPLE 43 (+/−) cisN-[1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thien-1-yl]-N′-(5-cyano-2-pyridinyl)-urea

a) cis ethyl ester1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylic acid,(1S,1aS,6bR) or (1R,1aR,6bS)

Ethyl diazoacetate is added slowly to 10 g of thiophene at 140° C. Thereaction was checked by gas chromatography and stopped after 7 hours.The residue is purified by flash chromatography (5% ether in hexane).The cis isomer (917 mg, Rdt=6%) was identified by NMR spectroscopy.

Reference: Badger G. M. et al, J. Chem. Soc., 1958, 1179-1184.

Badger G. M. et al, J. Chem. Soc., 1958, 4777-4779.

b) cis 1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylicacid, (1S,1aS,6bR) or (1R,1aR,6bS)

A mixture of the cis isomer (443 mg), LiOH (193 mg) in 15 ml ofmethanol/25% H₂O is refluxed for 1 hour. After evaporation of thesolvent under vacuum, the residue is dissolved in water and washed withether. The water phase is acidified with concentrated HCl, and extractedtwice with dichloromethane. After drying, the organic phase isevaporated and gave the desired acid (313.6 mg). Rdt=81%.

c) (+/−) cisN-[1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thien-1-yl]-N′-(5-cyano-2-pyridinyl)-urea

The cis acid (313 mg) was refluxed for 4 hours in toluene (20 ml) inpresence of Et₃N (0.25 ml), diphenyl phosphoryl azide (0.3 ml) and2-amino 6-cyanopyridine (220 mg). After cooling, the toluene phase waswashed with water, followed by a solution of HCl (0.01 M). The organicphase was dried and evaporated. The residue was purified by flashchromatography (EtOAc 2/Hexane 1) and gave 10 mg of the desiredcompound. Rdt=2%.

¹H (DMSO-d₆): 3.32 (1H, m); 3.39 (1H, td, 8.05, 7.69); 3.52 (1H, dd,7.69, 6.22); 7.08 (1H, td, 7.32, 1.1); 7.15 (1H, td, 7.32, 1.1); 7.22(1H, dd, 8.4, 0.8); 7.39 (2H, m); 7.50 (1H, NH); 8.00 (1H, dd, 8.79,2.2); 8.23 (1H, d, 2.2); 9.76 (1H, NH)

¹³C (DMSO-d₆): 25.6 (CH), 29.5 (CH), 33.7 (CH), 101.5 (C), 112.1 (CH),118.0 (C), 122.1 (CH), 124.9 (CH), 127.3 (CH), 128.0 (CH), 136.3 (C),141.7 (CH), 143.7 (C), 151.6 (CH), 155.1 (C), 156.1 (C)

Mass: 310 (M+2), 309 (M+H)

EXAMPLE 44(−)-cis-1-(5-Chloro-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropac[c]chromen-1-yl)-urea

This compound was prepared analogously to Example 1c but using chiral(+)−cis-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-carboxylicacid (see Example 42e) (1.3 g, 5.75 mmol). The silica gel purifiedproduct was recrystallized from acetonitrile to give 0.95 g (47%) of thetitle product. Absolute stereochemical configuration assigned as forExample 30.

¹H-NMR (CDCl₃): 9.25 (broad s, 1H), 8.67 (s, 1H), 7.79 (d, 1H), 7.48(dd, 1H), 6.92-6.86 (m, 1H), 6.71 (d, 1H), 6.65-6.60 (m, 1H), 4.45 (dd,1H), 4.34 (dd, 1H), 3.80 (q, 1H), 2.61 (t, 1H), 2.00-1.98 (m, 1H).

EXAMPLE 45(−)-cis-1-(5-Cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

(+)-cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (see example 42e) (1.18 g, 5.2 mmol), diphenylphosphorylazide [1340μL, 6.3 mmol (d=1.277)], triethylamine (870 μL, 6.3 mmol) and2-amino-5-cyanopyridine (740 mg, 6.3 mmol) were dissolved in toluene (15mL) and refluxed for 4 h. The solvent was then removed in vacuo and thecrude product was dissolved in ether and washed (3×100 mL 0.01 M HCl)and purified by chromatography (silica gel, 0→1% MeOH in ether) to givepure(−)-cis-1-(5-cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea(1.1 g, 64%). ee 92% as determined by HPLC on a Chiral AGP column,eluent 11% acetonitrile in sodium phosphate buffer, flow 0.9 mL/min.Absolute stereochemical configuration assigned as for Example 30.

¹H-NMR (CDCl₃): 9 (s, NH), 8.42 (s, NH), 8.16 (d, 1H), 7.72 (dd, 1H),6.97-6.76 (m, 2H), 6.69-6.61 (m, 1H), 4.47 (dd, 1H), 4.31 (dd, 1H), 3.75(m, 1H), 2.65 (t, 1H), 2.05-1.96 (m, 1H).

EXAMPLE 46(−)-cis-1-(5-cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-thiourea

(+)-cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid (2.2 g, 9.7 mmol), DPPA [2380 μl, 10.7 mmol 97%( d=1.277)] and TEA(1510 μl, 11.7 mmol) was refluxed in toluene (20 ml) for 2 h. Dioxane(26 mL) and HCl_((aq)) (26 mL, 6M) was then added and the reactionmixture was left for 1-2 h. At 50° C. Water (50 mL) was added and thewater phase was washed with Ether (2×25 mL) and then made alkaline withammonia_((aq)). Extraction with dichioromethane and drying gave theintermediate4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1ylamine (1.37 g,71%), which was directly treated with 6-isothiocyanato-nicotinonitrile(1.25 g, 7.7 mmol) in acetonitrile (2 mL) at RT over the weekend. Theprecipitated crystals were filtrated off and the solvent removed invacuo and chromatographed (silica, 20% ether in pentane). The productobtained was combined with the crystals and the crude product (900 mg)was re-crystallised (ethanol-acetone) to give pure(−)-cis-1-(5-cyano-pyridin-2-yl)-3-(4,7-difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]-chromen-1-yl)-thiourea(590 mg 18%). Absolute stereochemical configuration assigned as forExample 30.

¹H-NMR (CDCl₃-MeOD): 8.1 (d, 1H), 7.77 (dd, 1H), 6.99-6.91 (m, 1H), 6.74(dd, 1H) 6.73-6.66 (m, 1H), 4.48 (dd, 1H), 4.33 (dd, 1H), 4.20 ( dd,1H), 2.78(t, 1H), 2.16-2.1 (m, 1H).

EXAMPLE 47(±)-cis-1-(5-bromopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea

a) 1-(4-Fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.

To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 mL) at 0° C., wasadded 1-(4-fluoro-2-hydroxy-phenyl)-propan-1-one (1.68 g, 10 mmol) inDMF (5 mL). After 15 min at 0° C., was 3-bromo-propyne (3.02 g, 20 mmol)added to the reaction mixture. After 1 h at 0° C., was the reactionmixture allowed to assume room temperature. The reaction mixture wasextracted with H₂O (100 mL). The H₂O phase was washed with Et₂O (3×100mL) and the solvent of the combined organic phases was removed underreduced pressure. The crude product was purified by columnchromatography (silica gel, CH₂Cl₂), to give 1.40 g (68%) of1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one.

¹H-NMR (CDCl₃): 7.64 (dd, 1H), 6.69 (dd, 1H), 6.60 (ddd, 1H), 4.68 (d,2H), 2.85 (q, 2H), 2.58 (t, 1H), 1.03 (t, 3H).

b) 1-(5-Fluoro-2H-chromen-8-yl)-propan-1-one.

1-(5-Fluoro-2H-chromen-8-yl)-propan-1-one was synthesized analagously toExample 3b from 1-(4-fluoro-2-prop-2-ynyloxy-phenyl)-propan-1-one (1.34g, 6.5 mmol), to give 619 mg (46%) of1-(5-fluoro-2H-chromen-8-yl)-propan-1-one.

¹H-NMR (CDCl₃): 7.60 (dd, 1H), 6.67-6.58 (m, 2H), 5.86 (dt, 1H), 4.76(dd, 2H), 2.93 (q, 2H), 1.23 (t, 3H).

c)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester.

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester was synthesized according to method 3c) from1-(5-fluoro-2H-chromen-8-yl)-propan-1-one (619 mg, 3 mmol), to give 142mg (16%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester and(±)-trans-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester as a byproduct.

¹H-NMR (CDCl₃): 7.59 (dd, 1H), 6.65 (m, 1H), 4.50-4.46 (m, 2H), 3.95 (q,2H); 2.89 (q, 2H), 2.57 (dd, 1H), 2.20 (dd, 1H), 1.13-1.03 (m, 1H),1.12-1.01 (m, 6H).

d)(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid.

(±)-cis-7-Fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid was synthesized analogously to Example 1b from(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid ethyl ester (140.3 mg, 0.48 mmol), to give 83 mg (65%) of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid as a white solid. The crude product was purified by columnchromatography (silica gel, 1→5% MeOH in CH₂Cl₂).

¹H-NMR (DMSO-d₆): 12.15 (brs, 1H), 7.46 (dd, 1H), 6.78 (dd, 1H), 4.57(dd, 1H), 4.43 (dd, 1H), 2.93-2.80 (m, 2H), 2.55 (dd, 1H), 2.24 (dd,1H), 2.20-2.10 (m, 1H), 1.02 (t, 3H).

e)(±)-cis-1-(5-bromopyridin-2-yl)-3-(7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromen-1-yl)-urea.

The title compound is synthesized analogously to example 1c) by reacting1 equivalent of(±)-cis-7-fluoro-4-propionyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid and 1 eq of triethylamine in toluene with 1 eq ofdiphenylphosphoryl azide for 30 minutes at room temperature. Thereaction mixture is heated to 120° C. and an approximately equimolarsolution of 2-amino-5-bromopyridine is added. After 3 hours the solutionis allowed to assume room temperature and the title compound extractedas shown above.

EXAMPLE 48(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

a) Iodo-3-oxabicyclo[3.1.0]hexan-2-one

The title compound is synthesised in the depicted stereochemistry asdescribed in Doyle J Amer Chem Soc 117 (21) 5763-5775 (1993)

b) Iodo-2-methoxy-3-oxabicyclo[3,1,0]hexane

The title compound is synthesised in the depicted stereochemistry asdescribed in Martin et al Tett Lett 39 1521-1524 (1998).

c)(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

2,4-diflouroanisol (90 mg, 0.62 mmol) was dissolved in anhydrous,degassed, THF (7 ml) and cooled to −78° C. under N₂. nBuLi, 2.5 M inhexane, (0.30 ml, 0.77 mmol) was added and the reaction mixture wasstirred at −78° C. for 2 hrs. ZnCl₂ (150 mg, 1.1 mmol), as a solution inanhydrous THF (7 ml), was added and the reaction mixture was allowed towarm to ambient temperature for 2 hrs. Iodo-2-methoxy-3-oxabicyclohexane(150 mg, 0.63 mmol), Pd (OAc)₂ (1.5 mg, 6.2 μmol), and ligandTris(2,4-di-tert-butylphenyl)phosphite (40 mg, 62 μmol) were mixed inanhydrous THF (7 ml) and added to the reaction mixture. The reactionmixture was heated at reflux for 3 days and quenched with H₂O. Diethylether was added and the layers were separated, the organic layer waswashed with H₂O and aq. sat. NaCl, dried over MgSO₄, filtered andconcentrated to give the title compound, otherwise denoted2,4-di-fluoro-5-(cyclopropylacetal)anisol. Column chromatography onsilica (EtOAc/Hexane 1:3) gave (4) 50 mg, 31%.

¹H NMR (CDCl₃) δ (ppm): 6.88-6.94 (m, 1H, ArH), 6.68-6.73 (m, 1H, ArH),4.82 (s, 1H, CHOCH₃), 3.97-3.98 (m, 1H, CHOCH) 3.94 (s, 3H, OCH₃),3.79-3.81 (m, 1H, CHOCH) 3.30 (s, 3H, OCH₃), 2.13-2.19 (m, 2H,2×CH-cyclopropyl), 1.89 (tr, J=7.81 Hz, 1H, CH cyclopropyl).

EXAMPLE 49cis-4,7-Difluoro-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-1-carboxylicacid

BBr₃ 1M solution in CH₂Cl₂ (5.8 ml; 5.8 mmol 2.1 eq) was added tostarting lactone,(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-onefrom example 42c) (0.66 g; 2.75 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h. Acetonitrile (5.8 ml) was added and stirringwas continued for 3 h at 0° C. The reaction mixture was quenched byaddition of water and the organic phase was separated. Water phase wasextracted with CH₂Cl₂ and combined organic phases were evaporated. NaOH(0.33 g; 8.25 mmol; 3 eq) in water (˜5 ml) was added to the resultedresidue and stirred at 80° C. for 45 min. The reaction mixture wasextracted with ether to remove none acidic impurities. The residualether in water phase was evaporated in vacuo and conc. HCl was added topH of ˜3. After ˜1 h the solid was filtered off yielding 0.497 g (80%)of crude final acid as brownish solid. The crude acid was dissolved in 6ml of EtOH/H₂O (40/60 v/v) and treated with activated carbon. The hotsolution was filtered and left for crystallization. Yield 0.4 g (64%).

EXAMPLE 50N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-fluoro-2-pyridinyl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 2-amino-5-fluoropyridine (28 mg, 1.1eq), DPPA (0.054 ml, 1.1 eq). The reaction mixture was then heated atstirring at 110° C. for 3 h. The reaction mixture was concentrated byrotary evaporation and purified by column chromatography on silica (50g, ethylacetate/hexane 1:1) to give 30 mg of the product as white solid.

¹H-NMR (DMSO-d₆): 9.34 (brs, ˜1H), 7.85 (brd, 2H), 7.6 (d t, 1H), 7.33(dd, 1H), 7.06 (m, 1H), 6.77 (dt, 1H), 4.29 (m, 2H), 3.48 (m, 1H), 2.48(m, 1H/overlapped with DMSO signal), 2.00 (m, 1H). LC-MS: M⁺336

EXAMPLE 51N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-iodo-2-pyridinyl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 2-amino-5-iodopyridine (54 mg, 1.1eq), DPPA (0.054 ml, 1.1 eq). The reaction mixture was then heated atstirring at 110° C. for 3 h. The reaction mixture was concentrated byrotary evaporation and purified by column chromatography on silica (50g, ethylacetate/hexane 1:1) to give 35 mg of the product as white solid.

¹H-NMR (DMSO-d₆): 9.4 (br s, ˜1H), 8.07 (d, 1H), 8.02 (br s, ˜1H), 7.91(dd, 1H), 7.11 (d, 1H), 7.06 (m, 1H), 6.77 (dt, 1H), 4.29 (br d, 2H),3.5 (m, 1H), 2.46 (m, 1H/overlapped with DMSO signal), 2.00 (m, 1H).LC-MS: M⁺444.

EXAMPLE 52N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(3-isoxazolyl)urea

(1S,laR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 3-aminoisoxazole (0.018 ml, 1.1 eq),DPPA (0.054 ml, 1.1 eq). The reaction mixture was then heated atstirring at 110° C. for 3 h. The reaction mixture was concentrated byrotary evaporation and purified by column chromatography on silica (50g, ethylacetate/hexane 1:1) to give 10 mg of the product as white solid.

¹H-NMR (DMSO-d₆): 9.45 (br s, ˜1H), 8.6 (d, 1H), 7.06 (m, 1H), 6.75 (dt,1H), 6.63 (d, 1H), 6.33 (br s, ˜1H), 4.29 (m, 2H), 3.37 (overlapped withwater signal), 2.43 (m, 1H), 1.98 (m, 1H). LC-MS: M⁺308.

EXAMPLE 53N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq),2-amino-4-(4-chlorophenyl)-1,3-thiazole (52 mg, 1.1 eq), DPPA (0.054 ml,1.1 eq). The reaction mixture was then heated at stirring at 110° C. for3 h. The reaction mixture was concentrated by rotary evaporation and theproduct was crystallized from ethanol and collected by filtration togive 50 mg of the product as white solid.

¹H-NMR (CDCl₃): 10.32 (br s, ˜1H), 7.68 (d, 2H), 7.37 ( s, 1H), 7.32 (d,2H), 6.96 (s, 1H), 6.87 (m, 1H), 6.62 (dt, 1H), 4.44 (dd, 1H), 4.33 (dd,1H), 3.53 (m, 1H), 2.56 (m, ˜1H), 1.96 (m, 1H). LC-MS: M⁺434.

EXAMPLE 54N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(6-fluoro-1,3-benzothiazol-2-yl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 2-amino-6-fluoro-1,3-benzothiazole (41mg, 1.1 eq), DPPA (0.054 ml, 1.1 eq). The reaction mixture was thenheated at stirring at 110° C. for 3 h. The reaction mixture wasconcentrated by rotary evaporation and the product was crystallized fromethanol and collected by filtration to give 20 mg of the product aswhite solid.

¹H-NMR (CDCl₃): 10.58 (br s, ˜1H), 7.78 (br d, 1H), 7.52 ( dd, 1H), 7.45(dd, 1H), 7.05 (dt, 1H), 6.94 (m, 1H), 6.65 (dt, 1H), 4.44 (dd, 1H),4.33 (dd, 1H), 3.53 (m, 1H), 2.58 (m, ˜1H), 2.03 (m, 1H). LC-MS: M⁺434.

EXAMPLE 55N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(4-pyrimidinyl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 4-aminopyrimidine (25 mg, 1.1 eq),DPPA (0.054 ml, 1.1 eq). The reaction mixture was then heated withstirring at 110° C. for 3 h. The reaction mixture was concentrated byrotary evaporation and the product was crystallized from ethanol andcollected by filtration to give 20 mg of the product as white solid.

¹H-NMR (DMSO-d₆): 9.71 (br s, 1H), 8.4 (br s, 1H), 8.39 (d, 1H), 7.86(br s, 1H), 7.31 (d, 1H), 7.08 (m, 1H), 6.77 (dt, 1H), 4.31 (m, 2H),3.48 (m, 1H), 2.48 (m, 1H, overlapped with DMSO signal), 2.02 (m, 1H).

EXAMPLE 56N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(2-pyrazinyl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 4-aminopyrazine (25 mg, 1.1 eq), DPPA(0.054 ml, 1.1 eq). The reaction mixture was then heated with stirringat 110° C. for 3 h. The reaction mixture was concentrated by rotaryevaporation and the product was crystallized from ethanol and collectedby filtration to give 5 mg of the product as white solid.

¹H-NMR (DMSO-d₆): 9.57 (br s, 1H), 8.67 (br s, 1H), 8.10 (d, 1H), 7.95(br s, 1H), 7.64 (br s, 1H), 7.05 (m, 1H), 6.77 (dt, 1H), 4.31 (m, 2H),3.49 (m, 1H), 2.48 (m, ˜1H, overlapped with DMSO signal), 2.02 (m, 1H).

EXAMPLE 57N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-(5-cyclopropyl-1H-pyrazol-3-yl)urea

(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-1-carboxylicacid (50 mg, 0.22 mmol, ee ˜90%) was mixed with toluene (1 ml),triethylamine (0.034 ml, 1.1 eq), 3-amino-5-cyclopropyl-1H-pyrazole (30mg, 1.1 eq), DPPA (0.054 ml, 1.1 eq). The reaction mixture was thenheated at stirring at 110° C. for 3 h. The reaction mixture wasconcentrated by rotary evaporation and two compounds were separated bycolumn chromatography on silica (50 g, ethylacetate/hexane 1:3) to give3 mg of the title product. The structure assignment was proved by ¹³C,gHMBC, gHMQC and NOESY NMR experiments.

¹H-NMR (CDCl₃): 7.05 (br d, ˜1H), 6.88 (m, 1H), 6.64 (dt, 1H), 5.24 (d,1H), 4.49 (dd, 1H), 4.33 (dd, 1H), 3.63 (m, 1H), 2.61 (m, ˜2H), 1.99 (m,1H), 0.99 (m, 2H), 0.58 (m, 2H).

Biological Results

Extensive guidance on the assay of test compounds at the enzyme leveland in cell culture, including the isolation and/or selection of mutantHIV strains and mutant RT are found in DAIDS Virology Manual for HIVLaboratories complied by Division of AIDS, NIAID USA 1997. Resistancestudies, including rational for various drug escape mutants is describedin the HIV Resistance Collaborative Group Data Analysis Plan forResistance Studies, revised 31 Aug. 1999.

Compounds of the invention are assayed for HIV activity, for exampleusing multiple determinations with XTT in MT-4 cells (Weislow et al, JNat Cancer Inst 1989, vol 81 no 8, 577 et seq), preferably includingdeterminations in the presence of 40-50% human serum to indicate thecontribution of protein binding. In short the XTT assay uses human Tcell line MT4 cells grown in RPMI 1640 medium supplemented with 10%fetal calf serum (or 40-50% human serum as appropriate), penicillin andstreptomycin seeded into 96 well microplates (2·10⁴ cells/well) infectedwith 10-20 TCID₅₀ per well of HIV-1_(IIIB) (wild type) or mutant virus,such as those bearing RT IIe 100, Cys 181 or Asn 103 mutations. Seriallydiluted test compounds are added to respective wells and the cultureincubated at 37° C. in a CO₂ enriched atmosphere and the viability ofcells is determined at day five or six with XTT vital dye. Results aretypically presented as ED₅₀ μM.

Compounds of the invention were assayed in the above XTT assay usingwild type HIV-1_(IIIB) as shown in Table I:

TABLE 1 Example ED₅₀ (nM) Example 7 7 Example 16 6 Example 18 6 Example19 10 Example 20 7 Example 23 7 Example 24 20 Example 30 3 Example 312.5 Example 33 9 Example 43 2

Compounds are preferably potent against wild type virus and mutant HIVvirus, especially virus comprising drug escape mutations. Drug escapemutations are those which arise in patients due to the selectivepressure of a prior art antiviral and which confer enhanced resistanceto that antiviral. The above cited Data Analysis Plan outlines relevantdrug escape mutants for each of the antiviral classes currently on themarket. Drug escape clones are readily isolated from HIV patients whoare failing on a particular antiviral therapy. Alternatively thepreparation of RT mutations on a known genetic background is shown inWO97/27319, WO99/61658 and WO00/73511 which also show the use of suchmutants in sensitivity profiling.

K103 N is a particularly relevant drug escape mutant in the context ofNNRTI therapy and compounds of the invention preferably have a low ED₅₀against this mutant, especially in assays mimicking the presence ofhuman serum. Compounds of the invention, such as those exemplified aboveshow sub micromolar activities in such assays.

1. A compound of the formula V:

where R₄ and R₇ are independently fluoro, PG is lower alkyl, PG* islower alkyl or together with the adjacent O defines a keto group.
 2. Acompound according to claim 1, wherein PG is selected from the groupconsisting of isopropyl, ethyl and methyl.
 3. A compound according toclaim 1 wherein PG* together with the adjacent O defines a keto group.4. The compound according to claim 1, wherein PG* is selected from thegroup consisting of isopropyl, ethyl and methyl.
 5. A method to preparecompounds according to formula (I)

where R₂ is an optionally nitrogen-containing heterocycle, wherein thenitrogen is located at the 2 position relative to the urea bond; R₃ is Hor C₁-C₃ alkyl R₄-R₇ are independently selected from H, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloC₁-C₆ alkyl, C₁-C₆ alkanoyl, haloC₁-C₆alkanoyl, C₁-C₆ alkoxy, haloC₁-C₆ alkoxy, C₁-C₆ alkyloxy-C₁-C₆ alkyl,haloC₁-C₆ alkyloxy-C₁-C₆ alkyl hydroxy-C₁-C₆ alkyl, amino-C₁-C₆ alkyl,carboxy-C₁-C₆ alkyl, cyano-C₁-C₆ alkyl, amino, carboxy, carbamoyl,cyano, halo, hydroxy; comprising taking a compound of formula (V)

where R₄ and R₇ are independently halo, PG is lower alkyl, PG* is loweralkyl or together with the adjacent O defines a keto group through thesteps of: i) optionally transform PG* to define a keto group bytreatment of a compound of formula (V) wherein PG* is an hydroxyprotecting group with Jone's reagent; iia) reaction of a compound offormula (V) wherein PG* together with the adjacent O defines a ketogroup with BBr₃ in dichloromethane followed by addition of acetonitrileand finally sodium hydroxide to give the chromenecyclopropylcarboxylicacid; iib) alternatively, ring-opening of a compound of formula (V)wherein PG* together with the adjacent O defines a keto group, with HBrin conjuction with AcOH followed by subjection to NaGH to give thechromenecyclopropylcarboxylic acid; iii) conversion of the acid to thecorresponding acyl azide by treatment with DPPA followed by a Curtiusrearrangement to the isocyanate; iv) coupling of the isocyanate with therelevantly substituted 2-aminopyridine.